Pathway-to-drug matrix
The pathway diagrams light up per product; this table asks the inverse question. Across 86 pathways and 724 nodes, 182 nodes name a target in the corpus, 163 of those have at least one product and 19 have none. Pathways are sorted by how many druggable nodes still have no drug, which is where the design opportunities are.
Synthetic lethality: paired dependencies
Two genes are synthetically lethal when losing either alone is fine but losing both kills the cell. Cancers that have already lost one (a tumour suppressor you cannot put back) become uniquely dependent on the other, which you can drug. BRCA and PARP was the first proof; a dozen more pairs are now in trials.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| → PARP1, POLQ | PARP | Approved | |
| BRCA / HRD loss | BRCA1 / BRCA2 (HRD) | Approved | |
| TP53 loss, CCNE1 amp | TP53 | Approved | |
| → ATR | ATR | Druggable node, no drug in corpus | none |
| → PRMT5, MAT2A | PRMT5 (MTAP-deleted cancers) | Druggable node, no drug in corpus | none |
| → WEE1, PKMYT1, ATR | WEE1 | Druggable node, no drug in corpus | none |
| → WRN helicase | WRN helicase (MSI-high cancers) | Druggable node, no drug in corpus | none |
| ATM loss | no target in corpus | — | |
| CRISPR screens (DepMap) | no target in corpus | — | |
| MSI-H (MMR loss) | no target in corpus | — | |
| MTAP deletion | no target in corpus | — | |
| Resistance: restore lost path | no target in corpus | — | |
| Selective inhibitor | no target in corpus | — |
How drugs attack it, from the pathway page: PARP inhibitors for BRCA/HRD (approved in four cancers); MTA-cooperative PRMT5 inhibitors for MTAP-deleted tumours (mesothelioma, NSCLC, pancreatic; phase 1-2); WEE1 (azenosertib), PKMYT1 (lunresertib) and ATR (ceralasertib, camonsertib) inhibitors in TP53-mutant, CCNE1-amplified and ATM-deficient tumours; WRN inhibitors for MSI-H; SMARCA2 degraders for SMARCA4-deficient cancers.
DNA replication stress
Cancers copy their DNA too fast and with broken checkpoints, so replication forks stall and collapse. They survive only by leaning on emergency repair kinases such as ATR, CHK1, and WEE1, which is why blocking those kinases can be selectively lethal.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Oncogenes (MYC, cyclin E, RAS) | KRAS | Approved | |
| TP53 (lost) | TP53 | Approved | |
| ATR → CHK1 | ATR | Druggable node, no drug in corpus | none |
| WEE1 / PKMYT1 restrain CDK1 | WEE1 | Druggable node, no drug in corpus | none |
| Excess origin firing, short G1 | no target in corpus | — | |
| Fork collapse → DSBs | no target in corpus | — | |
| G2/M checkpoint | no target in corpus | — | |
| Mitotic catastrophe | no target in corpus | — | |
| Stalled forks, ssDNA gaps | no target in corpus | — |
How drugs attack it, from the pathway page: ATR inhibitors (ceralasertib, camonsertib) alone and with PARP inhibitors or IO; WEE1 (azenosertib) and PKMYT1 (lunresertib) inhibitors in CCNE1-amplified and TP53-mutant tumours; PARP inhibitors trap forks in HRD tumours (see DDR); Gemcitabine and other antimetabolites are classical replication-stress inducers.
p53 / RB / cell-cycle checkpoint
The p53 and RB checkpoints are the cell's brakes. p53 senses damage and stops the cell from copying itself; RB holds the cell at the G1 gate until CDK4/6 unlocks it. Cancers cut these brakes.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| CDK4/6 – cyclin D | CDK4/6 | Approved | |
| p53 | TP53 | Approved | |
| ATM / ATR | ATR | Druggable node, no drug in corpus | none |
| WEE1 (G2/M) | WEE1 | Druggable node, no drug in corpus | none |
| DNA damage | no target in corpus | — | |
| E2F | no target in corpus | — | |
| MDM2 | no target in corpus | — | |
| p21 | no target in corpus | — | |
| RB | no target in corpus | — | |
| S phase (DNA replication) | no target in corpus | — |
How drugs attack it, from the pathway page: CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib); WEE1 inhibitors (azenosertib) and PLK1 inhibitors in TP53-mutant tumours; MDM2 inhibitors (brigimadlin) in TP53-wild-type tumours; p53 Y220C reactivator rezatapopt; CDK2 inhibitors for CCNE1-amplified and CDK4/6-resistant disease.
The p53 network (guardian of the genome)
p53 is the cell's emergency coordinator. Damage, oncogene stress, or lack of oxygen switch it on; it then pauses division, orders repairs, or triggers suicide or permanent retirement. MDM2 keeps it switched off in healthy cells. Half of all cancers break p53 outright; many of the rest over-produce MDM2.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| p53 | TP53 | Approved | |
| PUMA, NOXA → apoptosis | BCL-2 | Approved | |
| DNA damage (ATM/ATR) | ATR | Druggable node, no drug in corpus | none |
| MDM2 / MDMX | MDM2 | Druggable node, no drug in corpus | none |
| Hypoxia, ribosome stress | no target in corpus | — | |
| Oncogene stress → ARF | no target in corpus | — | |
| p21 → arrest | no target in corpus | — | |
| Senescence, repair | no target in corpus | — | |
| TP53 mutation (~50%) | no target in corpus | — |
How drugs attack it, from the pathway page: MDM2 inhibitors (brigimadlin, milademetan, navtemadlin) for TP53-wild-type, MDM2-amplified tumours; Mutant p53 reactivators: rezatapopt (Y220C); eprenetapopt failed in phase 3 MDS; TP53-mutant tumours are approached via WEE1, ATR, PLK1 dependence and via p53-independent chemotherapy; TP53 status as biomarker: del17p CLL, MDS/AML risk, Li-Fraumeni surveillance.
Double-strand break repair: HR versus end joining
A break through both strands of DNA is the most dangerous lesion a cell faces. Two crews compete to fix it: homologous recombination copies the answer from the sister chromosome (accurate, needs BRCA), while end joining simply glues the ends (fast, sloppy). Which crew wins decides whether PARP inhibitors and radiation kill the cell.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| PALB2–BRCA2 → RAD51 | BRCA1 / BRCA2 (HRD) | Approved | |
| PARP trapping → breaks | PARP | Approved | |
| Resection: BRCA1–CtIP | BRCA1 / BRCA2 (HRD) | Approved | |
| MRN → ATM → CHK2 | ATR | Druggable node, no drug in corpus | none |
| 53BP1–Shieldin (protect) | no target in corpus | — | |
| Accurate HR (sister copy) | no target in corpus | — | |
| Double-strand break | no target in corpus | — | |
| Error-prone joining | no target in corpus | — | |
| NHEJ: Ku, DNA-PKcs, LIG4 | no target in corpus | — | |
| POLQ end joining (backup) | no target in corpus | — |
How drugs attack it, from the pathway page: PARP inhibitors (olaparib, niraparib, rucaparib, talazoparib) in BRCA/HRD ovarian, breast, prostate, pancreatic cancer; Platinum chemotherapy and radiation add breaks HR-deficient cells cannot fix; POLQ inhibitors (novobiocin analogues), ATR inhibitors after ATM loss, DNA-PK inhibitors with radiotherapy (trials); HRD testing (genomic scars, BRCA sequencing) and RAD51 foci assays select patients; reversion mutations detected in ctDNA flag resistance.
Nutrient competition & metabolic immunosuppression
Tumours and immune cells eat from the same plate. Cancer cells hoard glucose and glutamine, dump lactate and acid, and burn tryptophan and arginine into by-products that paralyse T cells. The tumour wins the food fight, and the immune system loses before it has fired a shot.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Arginase (MDSC, TAM) | CSF1R | Approved | |
| Hypoxia | HIF-2α | Approved | |
| T-cell / NK dysfunction | PD-1 | Approved | |
| CD39 → CD73 → adenosine | CD73 / adenosine axis | Druggable node, no drug in corpus | none |
| Glucose, glutamine depleted | no target in corpus | — | |
| Glycolytic tumour cell | no target in corpus | — | |
| IDO1 → kynurenine | no target in corpus | — | |
| Lactate, acidity (MCT4) | no target in corpus | — | |
| M2 macrophage polarisation | no target in corpus | — |
How drugs attack it, from the pathway page: IDO1 inhibitor epacadostat failed with pembrolizumab in melanoma (ECHO-301); lesson on phase 2 mirages; Adenosine axis: CD73 antibodies (oleclumab) and A2A antagonists, modest activity so far; Arginase inhibitors and glutamine antagonists (DRP-104) designed to spare T cells; Vessel normalisation and hypoxia relief; metabolically armoured CAR-T; diet trials.
The cell-cycle engine (cyclins & CDKs)
Cell division runs on a clock made of cyclins and their kinases (CDKs), each pair firing in order: D-CDK4/6 to leave rest, E-CDK2 to start copying DNA, A-CDK2 to finish, B-CDK1 to divide. Cancers speed the clock; CDK inhibitors slow it.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Cyclin D – CDK4/6 | CDK4/6 | Approved | |
| Mitogens (ER, RTK, RAS) | Estrogen receptor (ERα) | Approved | |
| p21 / p27 | TP53 | Approved | |
| WEE1 / PKMYT1 | WEE1 | Druggable node, no drug in corpus | none |
| Cyclin B – CDK1 | no target in corpus | — | |
| Cyclin E – CDK2 | no target in corpus | — | |
| Mitosis | no target in corpus | — | |
| p16 (CDKN2A) | no target in corpus | — | |
| RB → E2F released | no target in corpus | — | |
| S phase (cyclin A) | no target in corpus | — |
How drugs attack it, from the pathway page: CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) in HR+ breast cancer; CDK4-selective atirmociclib to spare neutrophils; CDK2 inhibitors for CCNE1-amplified and CDK4/6-resistant disease (trials); WEE1 (azenosertib) and PKMYT1 (lunresertib) inhibitors force premature mitosis in CCNE1-amplified or TP53-mutant cells; CDK7 and CDK9 inhibitors hit transcription as well as the cycle.
Transcriptional machinery & addiction
Cancer cells run a few genes (MYC, their lineage factors, their fusion oncogenes) at extreme volume from giant control regions called super-enhancers. The amplifiers, BRD4, CDK7, CDK9 and Mediator, are the same in every cell, but cancers are unusually dependent on them, and that dependence is druggable.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Lineage TFs (ER, AR, ASCL1) | Androgen receptor | Approved | |
| Menin–KMT2A (AML) | Menin | Approved | |
| MYC, MCL-1 (short-lived) | BCL-2 | Approved | |
| Fusion TFs (EWSR1-FLI1) | EWSR1-FLI1 fusion | Druggable node, no drug in corpus | none |
| BRD4, Mediator, p300 | no target in corpus | — | |
| CDK7 (TFIIH) initiation | no target in corpus | — | |
| CDK9 (P-TEFb) elongation | no target in corpus | — | |
| RNA Pol II | no target in corpus | — | |
| Super-enhancer | no target in corpus | — |
How drugs attack it, from the pathway page: Nuclear receptor drugs (endocrine therapy, ARPIs, SERDs, PROTAC vepdegestrant) are transcription drugs; Menin inhibitors revumenib and ziftomenib in KMT2A-rearranged and NPM1-mutant AML; BET inhibitors and BET/CBP degraders; CDK7 (samuraciclib) and CDK9 inhibitors in trials; Fusion-TF cancers (Ewing, NUT carcinoma) are the proving ground for transcriptional drugs.
DNA damage response & homologous recombination
The DNA damage response is the cell's set of repair crews. Single-strand breaks are patched by PARP; double-strand breaks by BRCA-dependent homologous recombination. Lose one crew and the cell survives; lose both and it dies. That is how PARP inhibitors work.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| BRCA1/2 – RAD51 (HR) | BRCA1 / BRCA2 (HRD) | Approved | |
| PARP1 | PARP | Approved | |
| ATR / CHK1 | ATR | Druggable node, no drug in corpus | none |
| Accurate repair | no target in corpus | — | |
| Double-strand break | no target in corpus | — | |
| Genomic collapse / death | no target in corpus | — | |
| NHEJ / POLQ (error-prone) | no target in corpus | — | |
| Replication fork collapse | no target in corpus | — | |
| Single-strand break | no target in corpus | — |
How drugs attack it, from the pathway page: PARP inhibitors in BRCA/HRD ovarian, breast, prostate, pancreatic cancer; Platinum chemotherapy (crosslinks) in HRD tumours; ATR inhibitors (ceralasertib) in ATM-deficient or PARP-resistant tumours; POLQ inhibitors (novobiocin analogues) in HRD; PARP1-selective saruparib to widen therapeutic window.
Ubiquitin–proteasome system & protein homeostasis
Cells tag unwanted proteins with a small marker called ubiquitin and feed them into a shredder, the proteasome. Myeloma cells, which make antibody in bulk, die if the shredder jams; and the newest drugs hijack the tagging machinery to make a cancer destroy its own oncoproteins.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Glues / PROTACs hijack E3 | Estrogen receptor (ERα) | Approved | |
| Substrate (IKZF1/3, p53, HIF) | HIF-2α | Approved | |
| E3 ligase (CRBN, VHL, MDM2) | MDM2 | Druggable node, no drug in corpus | none |
| 26S proteasome (β5) | no target in corpus | — | |
| Degradation | no target in corpus | — | |
| DUBs (USP7) | no target in corpus | — | |
| E1 → E2 ubiquitin | no target in corpus | — | |
| HSP90 chaperones | no target in corpus | — | |
| K48 ubiquitin chain | no target in corpus | — | |
| UPR, IκB → NF-κB | no target in corpus | — |
How drugs attack it, from the pathway page: Proteasome inhibitors bortezomib, carfilzomib, ixazomib in multiple myeloma and mantle cell lymphoma; Cereblon glues: lenalidomide, pomalidomide; CELMoDs iberdomide, mezigdomide, golcadomide; PROTACs: vepdegestrant (ER), BGB-16673 (BTK), AR degraders; degrader-antibody conjugates deliver them by antibody; Reactivating degradation of oncoproteins (MDM2 inhibition for p53) and blocking DUBs are in trials.
Mismatch repair & microsatellite instability
After DNA is copied, a proofreading crew fixes the letters the polymerase got wrong. Lose it and the genome fills with thousands of small errors, especially in repetitive stretches (microsatellites). Those errors make abnormal proteins that the immune system can see, which is why immunotherapy works so well in these cancers.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Checkpoint-inhibitor response | PD-1 | Approved | |
| WRN dependence | WRN helicase (MSI-high cancers) | Druggable node, no drug in corpus | none |
| Corrected DNA | no target in corpus | — | |
| EXO1, Pol δ resynthesis | no target in corpus | — | |
| Frameshift neoantigens | no target in corpus | — | |
| MMR loss (Lynch, MLH1 methylation) | no target in corpus | — | |
| MSI-H, hypermutation | no target in corpus | — | |
| MutLα (MLH1–PMS2) | no target in corpus | — | |
| MutSα (MSH2–MSH6) | no target in corpus | — | |
| Replication mismatch | no target in corpus | — |
How drugs attack it, from the pathway page: Tumour-agnostic pembrolizumab and dostarlimab for MSI-H/dMMR; nivolumab ± ipilimumab in colorectal cancer; Organ-sparing: dostarlimab alone cures most dMMR rectal cancers; neoadjuvant nivolumab-ipilimumab in dMMR colon cancer; Universal MMR/MSI testing of colorectal and endometrial cancer finds Lynch syndrome; colonoscopic surveillance and aspirin for carriers; WRN helicase inhibitors as synthetic-lethal therapy for MSI-H tumours (trials).
Circadian control
Cells run on a 24-hour clock that gates cell division, DNA repair, and drug metabolism. Cancers often break their clocks, and the time of day a drug or immunotherapy is given can change how well it works.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Cell-cycle gating (WEE1, MYC) | WEE1 | Druggable node, no drug in corpus | none |
| CLOCK/BMAL1 | no target in corpus | — | |
| DNA repair timing | no target in corpus | — | |
| PER/CRY (repress) | no target in corpus | — | |
| T-cell trafficking rhythm | no target in corpus | — | |
| Time-of-day drug response | no target in corpus | — |
How drugs attack it, from the pathway page: Morning versus afternoon immunotherapy dosing (prospective trials ongoing); Chronomodulated chemotherapy infusion; Clock-modulating compounds (preclinical).
Telomere maintenance & replicative immortality
Normal cells can divide only so many times because the protective caps on their chromosomes, telomeres, wear down. Cancers switch the cap-rebuilding enzyme telomerase back on, or find another way (ALT), so they can divide forever.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| ATR dependence (ALT) | ATR | Druggable node, no drug in corpus | none |
| ALT (ATRX/DAXX loss) | no target in corpus | — | |
| Each division shortens telomeres | no target in corpus | — | |
| Replicative immortality | no target in corpus | — | |
| Senescence / crisis | no target in corpus | — | |
| TERT reactivation (promoter mutation) | no target in corpus | — |
How drugs attack it, from the pathway page: Imetelstat (telomerase inhibitor) approved in MDS (2024); solid-tumour use unproven; ATR inhibitors in ALT-positive tumours; TERT promoter mutation as a urine/plasma biomarker (bladder, glioma).
Cold tumours: immune deserts and exclusion
Tumours come in three immune weathers: inflamed (T cells inside, checkpoint drugs work), excluded (T cells stuck at the edge), and desert (no T cells at all). Most common cancers are excluded or desert, and turning them 'hot' is the central problem of immunotherapy.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Abnormal vessels (VEGF) | VEGF / VEGFR | Approved | |
| Inflamed → PD-1 response | PD-1 | Approved | |
| Myeloid barrier | CSF1R | Approved | |
| β-catenin, PTEN loss → no cDC1 | PIK3CA / PI3K-alpha | Approved | |
| CXCL9/10 silenced (EZH2) | EZH2 | Phase 3 | |
| TGF-β CAFs, collagen | FAP | Phase 2 | |
| Immune desert | no target in corpus | — | |
| Immune exclusion | no target in corpus | — | |
| Low TMB, MHC loss | no target in corpus | — | |
| RT, STING, viruses, vaccines | no target in corpus | — |
How drugs attack it, from the pathway page: Radiotherapy, immunogenic chemotherapy and TOP1 ADCs to seed antigen and STING signalling; oncolytic viruses (T-VEC, RP1) and in situ vaccination; Anti-VEGF and PD-1×VEGF bispecifics open the vessel gate; FAP-, CXCR4- and TGF-β-directed agents (mostly modest so far); Epigenetic priming (EZH2, DNMT inhibitors) to restore chemokines; STING agonists intratumourally; Bypass the weather: T-cell engagers, CAR-T, TCR-T and vaccines that bring or make their own T cells.
Resistance routes: how a blocked pathway comes back
When a drug blocks a cancer's engine, the cancer has five ways back: change the part the drug binds, make more of it, take a side road, switch to a different engine altogether, or stop letting the drug in. Knowing which route a tumour took decides the next drug.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| 1 Target mutation / amp | KRAS | Approved | |
| 2 Bypass RTK (MET, HER3) | MET | Approved | |
| 3 Downstream (PIK3CA, RB1) | PIK3CA / PI3K-alpha | Approved | |
| 4 Lineage switch, persisters | DLL3 | Approved | |
| 5 Efflux, sanctuary, antigen loss | CD19 | Approved | |
| Drug blocks target | EGFR | Approved | |
| Next-gen, vertical combos, switch | no target in corpus | — | |
| Regrowth under therapy | no target in corpus | — | |
| Target → signal → growth | no target in corpus | — |
How drugs attack it, from the pathway page: Next-generation inhibitors for on-target mutations (osimertinib for T790M, lorlatinib for ALK G1202R, pirtobrutinib for BTK C481S, asciminib for T315I); Vertical and parallel combinations: BRAF+MEK, KRAS G12C + EGFR in CRC, CDK4/6 + endocrine + PI3K/AKT; Switching modality on progression: ADCs, radioligands, engagers and CAR-T are not cross-resistant with small molecules; Serial ctDNA to detect the route (C797S, MET amp, ESR1) and adaptive dosing; see the resistance atlas for every class.
Lineage plasticity & neuroendocrine transformation
Under pressure from a drug that blocks its identity (the androgen receptor in prostate cancer, EGFR in lung cancer), a tumour can change what kind of cell it is, becoming a small-cell neuroendocrine cancer that no longer needs the blocked signal. It is the ultimate escape: not a new mutation in the engine, but a new engine.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Adenocarcinoma (AR / EGFR) | Androgen receptor | Approved | |
| ARPI or EGFR TKI pressure | EGFR | Approved | |
| DLL3, B7-H3, SEZ6 surface | DLL3 | Approved | |
| TP53 + RB1 loss | TP53 | Approved | |
| SOX2, EZH2, ASCL1/NEUROD1 | EZH2 | Phase 3 | |
| AR / EGFR indifferent | no target in corpus | — | |
| EZH2 inhibitors block switch | no target in corpus | — | |
| Neuroendocrine / small-cell | no target in corpus | — | |
| Tarlatamab, platinum-etoposide | no target in corpus | — |
How drugs attack it, from the pathway page: Re-biopsy at progression when the clinical picture and markers diverge; ctDNA TP53/RB1 loss as a warning; DLL3 T-cell engager tarlatamab (SCLC; trials in neuroendocrine prostate cancer); B7-H3 and SEZ6 ADCs; EZH2 inhibitors (mevrometostat with enzalutamide, tazemetostat) to prevent or reverse plasticity; Aurora A inhibitors for MYCN/ASCL1-high states; Platinum-etoposide gives transient responses in transformed disease.
Receptor tyrosine kinase activation
Growth-factor receptors are antennas on the cell surface that pair up when a signal lands and switch on the growth relays inside. Cancers mutate, multiply, or fuse these antennas so they broadcast 'grow' with no signal at all. Most targeted drugs, antibodies and ADCs start here.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Bypass RTK (MET, HER3) | MET | Approved | |
| GRB2/SOS → RAS | KRAS | Approved | |
| Mutation, amp, fusion | ALK | Approved | |
| PI3K → AKT | PIK3CA / PI3K-alpha | Approved | |
| RTK dimer (EGFR, HER2, MET) | EGFR | Approved | |
| CBL → degradation | no target in corpus | — | |
| Ligand (EGF, HGF, NRG) | no target in corpus | — | |
| Proliferation, survival | no target in corpus | — | |
| SRC, STAT3, PLCγ | no target in corpus | — |
How drugs attack it, from the pathway page: TKIs by driver: osimertinib (EGFR), lorlatinib/alectinib (ALK), selpercatinib (RET), larotrectinib/entrectinib (NTRK), capmatinib/tepotinib (MET), imatinib (KIT/PDGFRA/BCR-ABL), zongertinib (HER2); Antibodies: trastuzumab/pertuzumab (HER2), cetuximab/panitumumab (EGFR); bispecifics amivantamab (EGFR×MET), zanidatamab, zenocutuzumab (HER2×HER3); ADCs use the receptor as an address: T-DXd, T-DM1, patritumab deruxtecan (HER3), telisotuzumab vedotin (MET); Combining with MET or downstream inhibitors closes bypass routes.
Tumour microenvironment (TME)
A tumour is not just cancer cells. It is a neighbourhood of fibroblasts, immune cells, blood vessels, nerves, and scaffolding that the cancer recruits and corrupts, and that decides whether drugs and immune cells can get in.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Abnormal vessels (VEGF) | VEGF / VEGFR | Approved | |
| Exhausted CD8 T cells (PD-1) | PD-1 | Approved | |
| Tregs (CTLA-4) | CTLA-4 | Approved | |
| CAFs (FAP+) | FAP | Phase 2 | |
| TAMs (CSF1R, CD47 axis) | CD47 | ||
| MDSCs | no target in corpus | — | |
| Nerves | no target in corpus | — | |
| Stiff ECM / desmoplasia | no target in corpus | — | |
| Tumour cells | no target in corpus | — |
How drugs attack it, from the pathway page: Checkpoint blockade (PD-1, CTLA-4, LAG-3) releases exhausted T cells; Anti-VEGF normalises vessels and improves infiltration; FAP-targeted imaging and radioligands attack CAFs; CSF1R, CD47/SIRPα, CXCR4, TGF-β, adenosine (A2A/CD73) agents target myeloid and stromal suppression; most have been modest so far; Radiation and oncolytic viruses convert excluded tumours.
Fibroblast activation, desmoplasia & matrix stiffness
Tumours recruit the body's repair cells, fibroblasts, and keep them in wound-healing mode forever. The scar tissue they lay down (desmoplasia) squeezes blood vessels shut, walls out immune cells, stiffens the tissue in a way that itself tells cancer cells to grow, and is why pancreatic cancer is so hard to treat.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Hedgehog (SMO) paradox | Smoothened (hedgehog pathway) | Approved | |
| iCAF (IL-6, CXCL12, LIF) | JAK2 | Approved | |
| T-cell exclusion | PD-1 | Approved | |
| myCAF (FAP, αSMA, collagen) | FAP | Phase 2 | |
| Collagen, HA, LOX crosslinks | no target in corpus | — | |
| Fibroblast / stellate cell | no target in corpus | — | |
| Growth, EMT, chemoresistance | no target in corpus | — | |
| Pressure: vessels collapse | no target in corpus | — | |
| Stiffness → FAK → YAP/TAZ | no target in corpus | — | |
| Tumour: TGF-β, PDGF, Hh, IL-1 | no target in corpus | — |
How drugs attack it, from the pathway page: FAP-targeted imaging (FAPI PET) and radioligands (FAP-2286) and FAP/LRRC15 CAR-T; Reprogramming: vitamin D analogues, losartan with chemoradiation (PDAC trials), IL-1/JAK inhibition for iCAFs; FAK inhibitors soften stroma and improve immunotherapy entry (trials); mechanobiology approaches; Vismodegib and PEGPH20 failed in PDAC: stromal depletion can accelerate disease.
Glutamine addiction
After glucose, glutamine is the tumour's favourite food. It feeds the energy cycle, donates nitrogen for making DNA letters, and makes the antioxidant glutathione. MYC- and KRAS-driven cancers eat so much of it that they starve the T cells next door.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| IDH → 2-HG / reductive | IDH1 / IDH2 | Approved | |
| mTORC1 sensing | AKT | Approved | |
| MYC, KRAS drive uptake | KRAS | Approved | |
| T cells starved | PD-1 | Approved | |
| Glutamate | no target in corpus | — | |
| Glutaminase (GLS) | no target in corpus | — | |
| Glutamine (SLC1A5) | no target in corpus | — | |
| Glutathione, NADPH | no target in corpus | — | |
| Nucleotides (N donor) | no target in corpus | — | |
| α-KG → TCA anaplerosis | no target in corpus | — |
How drugs attack it, from the pathway page: Asparaginase (depletes asparagine and glutamine) in ALL; Glutaminase inhibitor telaglenastat: negative in RCC and NSCLC; glutamine antagonist DRP-104 and ASCT2 blockers in early trials; IDH inhibitors (ivosidenib, vorasidenib) block the oncometabolite branch; Glutamine PET (18F-FGln) for glioma; metabolic imaging to pick fuel-dependent tumours.
Myeloid suppression: TAMs, MDSCs & don't-eat-me signals
Tumours recruit the body's clean-up cells (macrophages and immature myeloid cells) and re-train them as bodyguards. They switch off T cells, build vessels, and, when a therapeutic antibody flags a cancer cell for eating, are told 'don't eat me' by CD47 on its surface.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| CSF1, CCL2, G-CSF, VEGF | VEGF / VEGFR | Approved | |
| IL-10, TGF-β, PD-L1 | PD-L1 | Approved | |
| TAMs (CSF1R, TREM2) | CSF1R | Approved | |
| CD47 → SIRPα 'don't eat' | CD47 | ||
| Angiogenesis, metastasis | no target in corpus | — | |
| CD40 agonists, TLRs reprogram | no target in corpus | — | |
| MDSCs (arginase, ROS) | no target in corpus | — | |
| Monocytes, neutrophils | no target in corpus | — | |
| Phagocytosis (ADCP) | no target in corpus | — | |
| T cells suppressed | no target in corpus | — |
How drugs attack it, from the pathway page: CSF1R inhibitors pexidartinib and vimseltinib (approved in tenosynovial giant cell tumour; disappointing in cancer); CD47/SIRPα: magrolimab failed in AML/MDS; next-generation bispecifics and SIRPα-Fc in trials; CD40 agonists, TLR7/9 agonists, CXCR2/CCR2 blockade, PI3Kγ inhibitors as reprogrammers; CAR-macrophages, trained innate immunity (BCG) and antibody engineering for ADCP.
PD-1 / PD-L1 immune checkpoint & T-cell activation
How T cells decide to attack. A T cell needs to see the target (TCR-MHC) and get a 'go' signal (CD28). PD-1 and CTLA-4 are 'stop' signals; tumours exploit them. Checkpoint inhibitors remove the stop.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| CTLA-4 (stop) | CTLA-4 | Approved | |
| LAG-3 / TIGIT | LAG-3 | Approved | |
| PD-1 on T cell | PD-1 | Approved | |
| PD-L1 on tumour | PD-L1 | Approved | |
| Activated CD8 T cell | no target in corpus | — | |
| CD28 – B7 (go) | no target in corpus | — | |
| Dendritic cell (antigen + B7) | no target in corpus | — | |
| IFN-γ | no target in corpus | — | |
| TCR – peptide/MHC | no target in corpus | — | |
| Tumour cell killing | no target in corpus | — |
How drugs attack it, from the pathway page: Anti-PD-1 (pembrolizumab, nivolumab), anti-PD-L1 (atezolizumab, durvalumab); Anti-CTLA-4 (ipilimumab) ± anti-PD-1; Anti-LAG-3 (relatlimab) + nivolumab; PD-1×VEGF bispecifics (ivonescimab); Vaccines, T-cell engagers, and CAR-T supply signal 1 by other means.
Complement in cancer
Complement is a cascade of blood proteins that punches holes in things marked by antibodies and calls in inflammatory cells. Therapeutic antibodies such as rituximab use it to kill cancer cells; tumours defend themselves with shields (CD46, CD55, CD59), and the cascade's own by-products (C5a) can recruit the myeloid cells that protect the tumour.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| C5a → MDSC, neutrophils | CSF1R | Approved | |
| CD8 T cells suppressed | PD-1 | Approved | |
| IgG1 antibody (rituximab) | CD20 | Approved | |
| ADCC (NK, CD16) | no target in corpus | — | |
| Alternative / lectin | no target in corpus | — | |
| C1q classical route | no target in corpus | — | |
| C3 convertase → C3b | no target in corpus | — | |
| C5 → C5a + MAC (C5b-9) | no target in corpus | — | |
| CD46, CD55, CD59 shields | no target in corpus | — | |
| CDC lysis, opsonisation | no target in corpus | — |
How drugs attack it, from the pathway page: CD20 and CD38 antibodies (rituximab, obinutuzumab, daratumumab, isatuximab) kill partly through complement; Fc engineering tunes CDC versus ADCC; Blocking complement regulators (CD55/CD59) to restore CDC (preclinical); C5aR1 antagonists with checkpoint inhibitors to remove myeloid recruitment (early trials); Complement inhibition to manage infusion reactions and CAR-T inflammation.
DNA replication & origin licensing
Before a cell divides it must copy three billion letters of DNA exactly once. It does this by 'licensing' thousands of start points in advance and then firing them in waves. Cancers fire too many too fast, and many chemotherapies work by starving or jamming the copying machinery.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| CDK2 / DDK firing | CDK4/6 | Approved | |
| MYC, cyclin E: excess origins | KRAS | Approved | |
| TOP1 (chemo, ADC payloads) | TROP2 | Approved | |
| CMG helicase + Pol ε/δ | no target in corpus | — | |
| dNTP supply (RNR) | no target in corpus | — | |
| Geminin, CRL4-CDT2 | no target in corpus | — | |
| MCM2-7 loaded (licence) | no target in corpus | — | |
| ORC, CDC6, CDT1 | no target in corpus | — | |
| Replication fork | no target in corpus | — | |
| Replication stress | no target in corpus | — |
How drugs attack it, from the pathway page: Antimetabolites (5-FU, gemcitabine, methotrexate, pemetrexed, hydroxyurea, cytarabine) starve or terminate synthesis; Topoisomerase I poisons (irinotecan, topotecan) and their ADC payloads (SN-38, DXd, exatecan) trap the enzyme ahead of forks; Platinum crosslinks and alkylators block polymerases; ATR, CHK1, WEE1 inhibitors exploit the stress cancers create (see replication stress); CDC7 and POLQ inhibitors in trials.
Drug-tolerant persister cells
Even when a drug wipes out 99% of a tumour, a few cells survive without any resistance mutation: they go quiet, stop dividing, and wait. These persisters are the seed of relapse. They are hard to kill precisely because they are not doing much, but they have their own weaknesses.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Efflux, autophagy, BCL-XL | BCL-2 | Approved | |
| Targeted drug or chemo | EGFR | Approved | |
| KDM5A, H3K27me3, YAP, NF-κB | EZH2 | Phase 3 | |
| APOBEC → resistance mutation | no target in corpus | — | |
| Bulk tumour dies | no target in corpus | — | |
| FAO, low GSH → GPX4 dependence | no target in corpus | — | |
| Ferroptosis inducers | no target in corpus | — | |
| Persister: slow-cycling, reversible | no target in corpus | — | |
| Relapse (MRD → clinical) | no target in corpus | — | |
| Upfront combinations, holidays | no target in corpus | — |
How drugs attack it, from the pathway page: Upfront combinations that pre-empt persisters: osimertinib + chemotherapy (FLAURA2), amivantamab + lazertinib (MARIPOSA), BRAF + MEK + anti-PD-1; GPX4 and ferroptosis inducers, BCL-XL/MCL-1 inhibitors, KDM5 and EZH2 inhibitors (preclinical to phase 1); MRD-guided treatment: ctDNA clearance to de-escalate, persistence to intensify or switch; Intermittent or adaptive dosing to delay commitment to resistance (trials in melanoma and prostate cancer).
Epigenetic reprogramming
Cancer changes not just its genes but how they are read: chemical tags on DNA and histones silence guardians and awaken growth programmes. Unlike mutations, these changes are reversible, which is the hope behind epigenetic drugs.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| DNA methylation (DNMT, TET2, IDH/2-HG) | IDH1 / IDH2 | Approved | |
| Menin–KMT2A scaffold | Menin | Approved | |
| Histone marks (EZH2, KMT2A, H3K27M) | EZH2 | Phase 3 | |
| Active oncogenic programmes, persister states | no target in corpus | — | |
| Chromatin state | no target in corpus | — | |
| Readers (BET) & remodellers (SWI/SNF) | no target in corpus | — | |
| Silenced tumour suppressors, antigens | no target in corpus | — |
How drugs attack it, from the pathway page: Hypomethylating agents (azacitidine, decitabine) with venetoclax in AML; Menin inhibitors (revumenib, ziftomenib) in KMT2A/NPM1 leukaemia; IDH inhibitors reverse 2-HG hypermethylation; HDAC, BET, LSD1 inhibitors mostly in trials; epigenetic priming for immunotherapy.
FGF / FGFR signalling
Fibroblast growth factor receptors are growth antennas on the cell surface. Bladder cancer mutates FGFR3, bile duct cancer fuses FGFR2 to other genes, and stomach cancer overproduces FGFR2b; each has its own drug, and each brings a tell-tale side effect (high phosphate) because the same receptors control phosphate in the kidney.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| FGFR1-4 (FGFR2 fusions, FGFR3 mutations) | FGFR2 | Approved | |
| GAB1 → PI3K → AKT | PIK3CA / PI3K-alpha | Approved | |
| GRB2 / SOS → RAS → MAPK | KRAS | Approved | |
| FGF ligands (+ heparan sulphate / Klotho) | no target in corpus | — | |
| FGF23 → FGFR1 (kidney phosphate; drug side effect) | no target in corpus | — | |
| FRS2 | no target in corpus | — | |
| PLCγ / STAT | no target in corpus | — | |
| Proliferation, survival, angiogenesis | no target in corpus | — |
How drugs attack it, from the pathway page: Erdafitinib for FGFR3-altered advanced urothelial cancer after platinum and PD-1/PD-L1 therapy (THOR); Pemigatinib and futibatinib for FGFR2-fusion cholangiocarcinoma; futibatinib's covalent binding keeps activity against gatekeeper mutations; Bemarituzumab (anti-FGFR2b) with chemotherapy in FGFR2b-overexpressing gastric cancer (FORTITUDE-101); Phosphate binders and diet for hyperphosphataemia; eye examinations for central serous retinopathy; Selective FGFR2 and FGFR3 inhibitors under development to widen the therapeutic window.
Mitosis & the spindle assembly checkpoint
When a cell divides, a scaffold of microtubules (the spindle) pulls one copy of each chromosome to each side. A checkpoint holds the split until every chromosome is hooked on. Taxanes and vinca alkaloids freeze the spindle so the cell is stuck at this checkpoint until it dies.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Mitotic death (BCL-XL↓) | BCL-2 | Approved | |
| p53 arrest | TP53 | Approved | |
| Taxanes, vincas, MMAE, DM1 | HER2 | Approved | |
| Anaphase (separase) | no target in corpus | — | |
| APC/C–CDC20 | no target in corpus | — | |
| Centrosomes (Aurora A, PLK1) | no target in corpus | — | |
| Kinetochore attachment | no target in corpus | — | |
| SAC: MAD2, BUBR1, MPS1 | no target in corpus | — | |
| Slippage → tetraploid | no target in corpus | — | |
| Spindle microtubules | no target in corpus | — |
How drugs attack it, from the pathway page: Taxanes (paclitaxel, docetaxel, cabazitaxel), eribulin, vinca alkaloids (vincristine, vinblastine, vinorelbine); Tubulin-payload ADCs: MMAE (enfortumab, brentuximab, polatuzumab vedotin), DM1 (T-DM1), DM4 (mirvetuximab); Aurora A (alisertib), PLK1 and MPS1 inhibitors; KIF18A inhibitors for CIN-high tumours (trials); BCL-XL degraders to tip arrested cells into death.
Oncogenic viruses
About one cancer in eight worldwide is caused by a virus. HPV, hepatitis B and C, Epstein-Barr, HTLV-1, KSHV and Merkel cell polyomavirus each hijack the same brakes cancer normally has to mutate, which is why vaccines against HPV and HBV are among the most effective anti-cancer drugs ever made.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| p53 degraded | TP53 | Approved | |
| RB inactivated | CDK4/6 | Approved | |
| Viral antigens → IO response | PD-1 | Approved | |
| Chronic inflammation, cirrhosis | no target in corpus | — | |
| EBV LMP1, EBNA | no target in corpus | — | |
| HBV / HCV | no target in corpus | — | |
| HPV E6 / E7 | no target in corpus | — | |
| NF-κB, immortalisation | no target in corpus | — | |
| Vaccination, antivirals | no target in corpus | — | |
| Virus-driven cancer | no target in corpus | — |
How drugs attack it, from the pathway page: HPV vaccination (Gardasil 9) and HBV vaccination prevent the infection; HCV direct-acting antivirals and H. pylori eradication remove the driver; HPV testing and colposcopy find and excise precursor lesions; Checkpoint inhibitors work well in Merkel cell (avelumab, retifanlimab) and HPV+ cancers; EBV- and HPV-specific TCR-T and vaccines are in trials; Plasma EBV DNA screens for nasopharyngeal carcinoma and tracks response.
PI3K / AKT / mTOR
The cell's 'grow and survive' circuit. Growth signals from the surface switch on PI3K, which switches on AKT, which switches on mTOR, which builds proteins and blocks self-destruction.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| AKT | AKT | Approved | |
| PI3K (PIK3CA) | PIK3CA / PI3K-alpha | Approved | |
| RTK (HER2, EGFR) | HER2 | Approved | |
| FOXO / BAD (apoptosis) | no target in corpus | — | |
| mTORC1 | no target in corpus | — | |
| PIP3 | no target in corpus | — | |
| Protein synthesis, growth | no target in corpus | — | |
| PTEN | no target in corpus | — | |
| TSC1/2 | no target in corpus | — |
How drugs attack it, from the pathway page: PI3Kα inhibitors (alpelisib, inavolisib) for PIK3CA-mutant HR+ breast cancer; AKT inhibitor capivasertib for PIK3CA/AKT1/PTEN-altered breast and PTEN-deficient prostate cancer; mTOR inhibitor everolimus; Dual PI3K/mTOR gedatolisib (2026); Upstream: anti-HER2, anti-EGFR.
RAS / RAF / MEK / ERK (MAPK)
The RAS-MAPK pathway is the cell's 'divide' relay. A signal at the surface flips RAS on, which passes to RAF, MEK, and ERK, which tell the nucleus to make the cell divide. KRAS and BRAF mutations jam it in the on position.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| RAF (BRAF) | BRAF | Approved | |
| RAS (KRAS) | KRAS | Approved | |
| RTK (EGFR, ALK, RET, MET) | EGFR | Approved | |
| Cyclin D1, MYC → proliferation | no target in corpus | — | |
| DUSP / SPRY feedback | no target in corpus | — | |
| ERK1/2 | no target in corpus | — | |
| GRB2 / SOS1 | no target in corpus | — | |
| MEK1/2 | no target in corpus | — | |
| NF1 (GAP) | no target in corpus | — |
How drugs attack it, from the pathway page: KRAS G12C inhibitors (sotorasib, adagrasib) ± anti-EGFR in colorectal cancer; Pan-RAS(ON) inhibitor daraxonrasib (phase 3, pancreatic); BRAF + MEK inhibitors (dabrafenib/trametinib, encorafenib/binimetinib); Encorafenib + cetuximab (+ chemo) in BRAF V600E CRC; Upstream: EGFR, ALK, RET, MET, NTRK inhibitors and bispecifics.
T-cell exhaustion
T cells that see their target for weeks on end without winning gradually shut down: they raise a set of brakes (PD-1, LAG-3, TIM-3, TIGIT), lose their ability to kill, and eventually lock this state into their DNA. Checkpoint drugs rescue the ones that are only partly exhausted; the terminally exhausted are beyond reach.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| CAR-T exhaustion | CD19 | Approved | |
| Checkpoint blockade | LAG-3 | Approved | |
| PD-1, LAG-3, TIM-3, TIGIT | PD-1 | Approved | |
| Chronic antigen, no help | no target in corpus | — | |
| Cytokines, killing | no target in corpus | — | |
| DNMT3A epigenetic scar | no target in corpus | — | |
| TCF1+ progenitor (stem-like) | no target in corpus | — | |
| Terminally exhausted | no target in corpus | — | |
| TOX, NR4A, NFAT | no target in corpus | — | |
| Transitory effector | no target in corpus | — |
How drugs attack it, from the pathway page: Anti-PD-1/PD-L1; combinations with anti-LAG-3 (relatlimab-nivolumab, fianlimab) and anti-TIGIT (tiragolumab, mixed results); Earlier use (neoadjuvant) when the TCF1+ reservoir is larger; IL-2 variants and IL-15 superagonists to expand progenitors; CAR-T engineering: c-Jun overexpression, TET2/DNMT3A editing, transient rest, PD-1 knockout; Epigenetic drugs to reverse scarring (preclinical).
The angiogenic switch & tumour vessels
A tumour cannot grow beyond a couple of millimetres without its own blood supply. The 'switch' flips when the signals calling for new vessels (VEGF, FGF, angiopoietin) outweigh the ones holding them back (thrombospondin). The vessels that result are leaky and chaotic, which starves the tumour of oxygen, blocks drugs, and gives cancer cells a way out.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Hypoxia (HIF), RAS, p53 loss | HIF-2α | Approved | |
| TAMs, MDSCs (bypass) | CSF1R | Approved | |
| VEGF, FGF2, ANG2, PDGF | VEGF / VEGFR | Approved | |
| Angiogenic switch | no target in corpus | — | |
| Hypoxia, poor delivery, exit | no target in corpus | — | |
| Leaky, chaotic vessels | no target in corpus | — | |
| Pericytes (PDGFRβ) | no target in corpus | — | |
| Tip / stalk sprouting (VEGFR2) | no target in corpus | — | |
| TSP-1, endostatin | no target in corpus | — | |
| Vessel co-option | no target in corpus | — |
How drugs attack it, from the pathway page: Anti-VEGF antibodies (bevacizumab, ramucirumab) and VEGFR TKIs (axitinib, cabozantinib, lenvatinib, sunitinib, pazopanib, tivozanib, fruquintinib, regorafenib, sorafenib); Vascular normalisation windows for IO-VEGF combinations in RCC, HCC, endometrial cancer; PD-1×VEGF bispecific ivonescimab; HIF-2α inhibition upstream (belzutifan); multikinase inhibitors hit FGFR/PDGFR escape ligands; Vessel co-option limits anti-angiogenics in liver and brain metastases.
The cancer-immunity cycle
Seven steps the immune system must complete to kill a tumour: release of antigens, pick-up by dendritic cells, priming of T cells in lymph nodes, travel, entry into the tumour, recognition, and killing. Every immunotherapy pushes on one step; every escape blocks one.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| 3 Priming (CD28 / CTLA-4) | CTLA-4 | Approved | |
| 5 Infiltration | VEGF / VEGFR | Approved | |
| 7 Killing (PD-1 brake) | PD-1 | Approved | |
| 1 Antigen release | no target in corpus | — | |
| 2 DC capture (cDC1) | no target in corpus | — | |
| 4 Trafficking (CXCL9/10) | no target in corpus | — | |
| 6 Recognition (MHC-I) | no target in corpus | — | |
| Escape at any step | no target in corpus | — |
How drugs attack it, from the pathway page: Radiation, chemotherapy, oncolytic viruses and ADC payloads feed step 1 (immunogenic cell death); Vaccines and STING agonists load step 2; anti-CTLA-4 acts at step 3; Anti-VEGF and stromal agents open steps 4-5; Engagers, CAR-T and TCR-T replace step 6; anti-PD-1/PD-L1 releases step 7.
The pre-metastatic niche
Before a single cancer cell arrives, the primary tumour sends parcels ahead: tiny vesicles (exosomes) and hormones that recruit bone-marrow cells to a distant organ and remodel it into fertile soil. By the time the seed lands, the bed is already made.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| MDSCs, immune suppression | CSF1R | Approved | |
| Primary tumour (hypoxic) | HIF-2α | Approved | |
| VEGF, G-CSF, LOX, S100A8/9 | VEGF / VEGFR | Approved | |
| Arriving CTCs | no target in corpus | — | |
| Bone-marrow cells (VEGFR1+) | no target in corpus | — | |
| Colonisation | no target in corpus | — | |
| Exosomes (integrins, MIF) | no target in corpus | — | |
| Niche: fibronectin, MMP9, leaky | no target in corpus | — | |
| Resident cells: Kupffer, fibroblasts | no target in corpus | — |
How drugs attack it, from the pathway page: Adjuvant systemic therapy and ctDNA-guided escalation act during niche formation and early seeding; Exosome and integrin profiling to predict organ of relapse (research); exosome-based therapeutics in early development; LOX, CXCR2 and CCR2 inhibitors, and G-CSF neutralisation in models; Anti-VEGF has not prevented metastasis in adjuvant trials (bevacizumab in colon and breast), a cautionary result.
Antigen presentation & immune editing
How the immune system sees cancer, and how cancer learns to hide. Tumours display fragments of their proteins on MHC molecules; T cells kill the ones they recognise; the survivors are the ones that stopped showing fragments or switched on brakes.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| CD8 T cell (TCR) | CD3 | Approved | |
| PD-L1 induction | PD-L1 | Approved | |
| Dendritic cell cross-presentation | no target in corpus | — | |
| Escape: B2M/HLA loss, JAK mutation | no target in corpus | — | |
| IFN-γ → JAK1/2 → STAT1 | no target in corpus | — | |
| MHC-I / B2M loading | no target in corpus | — | |
| Peptide–MHC on surface | no target in corpus | — | |
| Proteasome → peptides | no target in corpus | — | |
| TAP transport | no target in corpus | — |
How drugs attack it, from the pathway page: Checkpoint inhibitors; personalised neoantigen vaccines (intismeran) supply antigen; T-cell engagers and CAR-T bypass MHC entirely; TCR-T and ImmTACs (tebentafusp) target intracellular antigens via peptide–HLA; Epigenetic drugs and interferon can re-express MHC; MHC-independent NK-cell therapies address MHC-loss escape.
Base excision repair, PARP & alkylation damage
Tens of thousands of times a day a single DNA letter is oxidised or chemically scarred. A small crew snips it out and PARP marks the nick so it gets sealed. PARP inhibitors do not just switch PARP off; they trap it on the DNA, turning a harmless nick into a lethal break when the cell copies its DNA.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| HR (BRCA) rescue | BRCA1 / BRCA2 (HRD) | Approved | |
| PARP1 → XRCC1 | PARP | Approved | |
| Fork collapse → DSB | no target in corpus | — | |
| Glycosylase → APE1 | no target in corpus | — | |
| MGMT direct reversal | no target in corpus | — | |
| Oxidised / alkylated base | no target in corpus | — | |
| PARP trapped on DNA | no target in corpus | — | |
| Pol β, LIG3 seal | no target in corpus | — | |
| Single-strand break | no target in corpus | — | |
| Temozolomide, radiation | no target in corpus | — |
How drugs attack it, from the pathway page: PARP inhibitors: talazoparib (strongest trapper), olaparib, niraparib, rucaparib; PARP1-selective saruparib; Temozolomide in MGMT-methylated glioblastoma; lomustine, dacarbazine as alkylators; PARP inhibitor + radiotherapy or + TMZ combinations, limited by marrow toxicity; PARP-radioligand combinations in trials; PARP PET imaging to quantify target.
BCR::ABL1 (Philadelphia chromosome)
Chronic myeloid leukaemia is caused by one broken gene: two chromosomes swap pieces and glue a kinase (ABL1) to a protein that forces it permanently on. Imatinib, the first drug to target it, turned a fatal disease into a manageable one, and later drugs cover the mutations that escape it.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| PI3K → AKT | PIK3CA / PI3K-alpha | Approved | |
| RAS → MAPK | KRAS | Approved | |
| BCR::ABL1 kinase (p210 / p190) | no target in corpus | — | |
| GRB2 / GAB2 | no target in corpus | — | |
| Proliferation, survival, genomic instability → CML, Ph+ ALL | no target in corpus | — | |
| Reactive oxygen species → new mutations | no target in corpus | — | |
| STAT5 | no target in corpus | — | |
| t(9;22) translocation | no target in corpus | — |
How drugs attack it, from the pathway page: Imatinib, the first-generation ATP-site inhibitor; dasatinib, nilotinib, bosutinib as more potent second-generation options; Ponatinib for the T315I gatekeeper mutation; Asciminib, an allosteric STAMP inhibitor, alone or with an ATP-site inhibitor against compound mutations; Molecular monitoring (BCR::ABL1 transcripts) to guide treatment-free remission attempts; In Ph-positive ALL: TKI with chemotherapy or with blinatumomab, and transplant for high-risk disease.
Cancer stem cells & phenotypic plasticity
Some cancer cells behave like stem cells: they can regrow the whole tumour, resist treatment, and switch identities. This plasticity explains why tumours come back and why some lung and prostate cancers transform into a different cancer type under therapy.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Lineage switch (NE transformation) | DLL3 | Approved | |
| EZH2, SWI/SNF, TP53/RB1 loss | EZH2 | Phase 3 | |
| Differentiated bulk | no target in corpus | — | |
| Mesenchymal / drug-tolerant persister | no target in corpus | — | |
| Stem-like state | no target in corpus | — | |
| Wnt / Notch / Hedgehog niche | no target in corpus | — |
How drugs attack it, from the pathway page: Differentiation therapy: ATRA/arsenic in APL (curative), menin inhibitors differentiate KMT2A/NPM1 leukaemias; EZH2, LSD1, and BET inhibitors to block plasticity (trials); DLL3-directed tarlatamab for neuroendocrine-transformed tumours; MRD-directed therapy to catch persisters before regrowth.
Cellular senescence
Damaged cells can stop dividing permanently instead of dying. That protects against cancer at first, but senescent cells linger, secrete inflammatory signals, and after chemotherapy can help tumours relapse, so removing them (senolytics) is a new strategy.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| p16 → RB | CDK4/6 | Approved | |
| p53 → p21 | TP53 | Approved | |
| Inflammation, relapse, resistance | no target in corpus | — | |
| Oncogene / therapy stress | no target in corpus | — | |
| SASP (IL-6, IL-8, MMPs) | no target in corpus | — | |
| Senolytics (BCL-XL, uPAR CAR-T) | no target in corpus | — | |
| Stable arrest | no target in corpus | — |
How drugs attack it, from the pathway page: Senescence-inducing therapy (CDK4/6 inhibitors, chemotherapy, radiation) followed by senolytics (one-two punch); Navitoclax and BCL-XL PROTACs; uPAR-targeted CAR-T (preclinical); SASP modulation with JAK inhibitors or IL-6 blockade.
Chromosomal instability & aneuploidy
Most cancers have the wrong number of chromosomes and keep shuffling them at every division. This chaos fuels evolution and drug resistance, but it also stresses the cell and can trigger immune alarms, a double edge that researchers are trying to exploit.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| ecDNA oncogene amplification | EGFR | Approved | |
| TP53 loss permits | TP53 | Approved | |
| Aneuploidy / karyotype heterogeneity | no target in corpus | — | |
| cGAS–STING | no target in corpus | — | |
| Chromosomal instability | no target in corpus | — | |
| Clonal evolution, resistance | no target in corpus | — | |
| Dependencies: KIF18A, SAC, BCL-XL | no target in corpus | — | |
| Micronuclei → cytosolic DNA | no target in corpus | — | |
| Mitotic errors, WGD | no target in corpus | — |
How drugs attack it, from the pathway page: KIF18A inhibitors (sovilnesib) selectively kill CIN-high cells; phase 1/2 in ovarian and TNBC; ecDNA-directed strategies (CHK1 inhibition, transcription–replication conflict) from the Cancer Grand Challenges eDyNAmiC team; STING pathway modulation; radiation exploits CIN; Aneuploidy scores (TRACERx) as prognostic biomarkers.
Drivers, passengers & the two-hit model
Of the thousands of mutations in a tumour, only a handful (typically 2-8) actually drive it. Drivers either jam an accelerator on (oncogenes, one hit is enough) or remove a brake (tumour suppressors, both copies must go). Everything else is a passenger along for the ride.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Mutation, amp, fusion | KRAS | Approved | |
| Tumour suppressor | TP53 | Approved | |
| 1st hit (germline/somatic) | no target in corpus | — | |
| 2nd hit: LOH, methylation | no target in corpus | — | |
| Brake lost (2 hits) | no target in corpus | — | |
| Clonal expansion | no target in corpus | — | |
| Oncogene ON (1 hit) | no target in corpus | — | |
| Passengers, neoantigens | no target in corpus | — | |
| Proto-oncogene | no target in corpus | — |
How drugs attack it, from the pathway page: Oncogene addiction is the basis of every targeted kinase inhibitor and of HER2 antibodies; Suppressor loss cannot be 'inhibited', so it is exploited indirectly: synthetic lethality (BRCA-PARP, MTAP-PRMT5), CDK4/6 for RB-intact, MDM2 for TP53-wild-type; Germline first hits drive surveillance and risk-reducing surgery in hereditary syndromes; Comprehensive genomic profiling separates drivers from passengers at diagnosis.
Drug efflux pumps (ABC transporters)
Cancer cells can install pumps in their outer membrane that throw chemotherapy back out as fast as it comes in. The same pumps guard the gut, brain and bone marrow in healthy tissue, which is why blocking them failed as a strategy and why drug designers now choose payloads the pumps cannot grip.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| EMT, hypoxia, NRF2 induce | KRAS | Approved | |
| Non-substrate payloads (DXd) | TROP2 | Approved | |
| ABCB1 (P-gp) | no target in corpus | — | |
| ABCG2 (BCRP), ABCC1 | no target in corpus | — | |
| BBB, stem cells, marrow | no target in corpus | — | |
| Cell death | no target in corpus | — | |
| Chemo / payload enters | no target in corpus | — | |
| Drug exported (ATP) | no target in corpus | — | |
| Sub-lethal intracellular dose | no target in corpus | — |
How drugs attack it, from the pathway page: Payload selection: DXd and exatecan (T-DXd, Dato-DXd, sac-TMT) retain activity where MMAE and SN-38 are pumped out; PBD dimers and radionuclides are pump-independent; Brain-penetrant TKIs engineered to evade P-gp (lorlatinib, tucatinib, osimertinib); P-gp inhibitors (valspodar, tariquidar, zosuquidar) failed in phase 3; a museum exhibit; Collateral sensitivity and MDR-selective compounds are experimental.
Extrinsic apoptosis (death receptors)
Immune cells kill by touch: they present FAS ligand or TRAIL to a target cell, whose death receptors then trigger self-destruction from the outside in. Tumours cut this wire by deleting the receptors or over-producing decoys and blockers.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| CTL / NK cell | CD3 | Approved | |
| tBID → mitochondria | BCL-2 | Approved | |
| Caspase-3/7 → death | no target in corpus | — | |
| Decoy receptors, c-FLIP | no target in corpus | — | |
| DISC: FADD, caspase-8 | no target in corpus | — | |
| FAS, DR4/DR5 | no target in corpus | — | |
| FASL, TRAIL | no target in corpus | — | |
| Perforin / granzyme B | no target in corpus | — | |
| XIAP (IAPs) | no target in corpus | — |
How drugs attack it, from the pathway page: Checkpoint inhibitors, engagers and CAR-T all ultimately act through this wire, so caspase-8 or FAS loss confers immune resistance; SMAC mimetics (IAP antagonists) lower the threshold; birinapant, xevinapant tested with chemoradiation; DR5 agonist antibodies and TRAIL-receptor engagers, largely inactive so far; BH3 mimetics engage the mitochondrial arm downstream of tBID.
Intravasation & circulating tumour cells
Getting into the bloodstream and surviving there is brutal: cells are ripped from their neighbours, battered by flow, and hunted by NK cells. Fewer than one in a thousand survive. The ones that do travel in clusters, wear a cloak of platelets, or ride with neutrophils. Liquid biopsies catch what is left.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Leaky vessels (VEGF) | VEGF / VEGFR | Approved | |
| TMEM doorway (macrophage) | CSF1R | Approved | |
| Anoikis (detachment death) | no target in corpus | — | |
| Clusters (plakoglobin, CD44) | no target in corpus | — | |
| Intravasation | no target in corpus | — | |
| Liquid biopsy detection | no target in corpus | — | |
| NK-cell clearance | no target in corpus | — | |
| Platelet cloak, NETs | no target in corpus | — | |
| Shear, oxidative stress | no target in corpus | — | |
| Surviving CTCs / clusters | no target in corpus | — |
How drugs attack it, from the pathway page: Liquid biopsy: CTC enumeration (CellSearch), ctDNA (Signatera, Guardant Reveal), fragmentomics for detection and MRD; Aspirin and low-molecular-weight heparin target platelet cloaking; aspirin reduces recurrence in PIK3CA-mutant colorectal cancer (ALASCCA); Anti-VEGF and CSF1R inhibition close TMEM doorways in models; Cluster-dissociating agents (digoxin analogues) and NK-boosting therapies are experimental.
Lipid synthesis, uptake & cholesterol
Dividing cells need membranes, and membranes are fat. Cancers switch on the fat-building enzymes most adult tissues keep off, and in fatty environments (breast, omentum, bone marrow) they also steal lipids from neighbouring fat cells. This links obesity to cancer and offers new drug targets.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Mevalonate → cholesterol | KRAS | Approved | |
| SREBP (mTORC1, hypoxia) | AKT | Approved | |
| ACC → malonyl-CoA | no target in corpus | — | |
| AMPK / LKB1 | no target in corpus | — | |
| CD36 uptake from adipocytes | no target in corpus | — | |
| Citrate → ACLY → acetyl-CoA | no target in corpus | — | |
| FASN → palmitate | no target in corpus | — | |
| Fatty acid oxidation (CPT1) | no target in corpus | — | |
| Obesity, insulin, IGF-1 | no target in corpus | — | |
| PUFA → ferroptosis | no target in corpus | — | |
| SCD1 → membranes | no target in corpus | — |
How drugs attack it, from the pathway page: FASN inhibitor denifanstat and SCD1 inhibitors in trials; statins repurposed with mostly negative randomised data; Weight management, GLP-1 agonists and bariatric surgery reduce obesity-related cancer incidence; Exercise and dietary pattern interventions during treatment; Ferroptosis inducers exploit the lipid composition of mesenchymal and persister cells.
Menin / KMT2A (HOXA9-MEIS1 axis)
In some leukaemias a broken chromatin protein (KMT2A, once called MLL) or a mutant NPM1 keeps embryonic growth genes (HOXA9, MEIS1) switched on, so blood cells never mature. Both need a partner called menin to stay on the DNA. Menin inhibitors pull the plug and the cells mature; the first was approved in 2024.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| FLT3 (co-mutated; co-target) | FLT3 | Approved | |
| Menin (MEN1) + LEDGF | Menin | Approved | |
| Complex bound at chromatin | no target in corpus | — | |
| Differentiation block → acute leukaemia | no target in corpus | — | |
| DOT1L (H3K79me) | no target in corpus | — | |
| HOXA9 / MEIS1 transcription | no target in corpus | — | |
| KMT2A fusion (MLL-r) | no target in corpus | — | |
| Mutant NPM1 (cytoplasmic) | no target in corpus | — |
How drugs attack it, from the pathway page: Revumenib for relapsed or refractory KMT2A-rearranged acute leukaemia (approved 2024) and NPM1-mutant AML; Ziftomenib for relapsed or refractory NPM1-mutant AML (approved 2025); Combinations with venetoclax plus azacitidine and with FLT3 inhibitors in front-line trials; Differentiation syndrome and QT prolongation need monitoring; MEN1 pocket mutations cause resistance; DOT1L inhibition (pinometostat) showed limited single-agent activity.
NK-cell recognition: missing self & stress ligands
Natural killer cells patrol for cells that have lost their identity papers (MHC-I) or that display stress flags. Cancers that hide from T cells by dropping MHC-I become visible to NK cells, unless they also shed the stress flags, wrap themselves in a second inhibitory badge (HLA-E), or soak the neighbourhood in TGF-β.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| CD16 ← IgG1 antibody (ADCC) | HER2 | Approved | |
| TIGIT vs DNAM-1 (CD155) | TIGIT | ||
| CAR-NK, IL-15, NK engagers | no target in corpus | — | |
| HLA-E → NKG2A (inhibit) | no target in corpus | — | |
| MHC-I → KIR (inhibit) | no target in corpus | — | |
| MICA shedding, TGF-β | no target in corpus | — | |
| MICA/B, ULBP → NKG2D | no target in corpus | — | |
| NK cell decision | no target in corpus | — | |
| Perforin, granzyme, IFN-γ | no target in corpus | — |
How drugs attack it, from the pathway page: IgG1 antibodies (trastuzumab, cetuximab, rituximab) recruit NK ADCC; afucosylated antibodies (obinutuzumab, margetuximab) bind CD16 harder; IL-15 superagonist nogapendekin alfa (BCG-unresponsive NMIBC); CAR-NK and NK engagers in trials; Anti-NKG2A (monalizumab) and anti-TIGIT (tiragolumab) release inhibitory checks, with mixed phase 3 results; NK-based therapies address MHC-I-loss escape from T-cell therapies.
Oestrogen receptor signalling
In hormone-positive breast cancer, oestrogen binds its receptor, which switches on genes that make the cell divide. Every endocrine therapy cuts this chain somewhere.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| CDK4/6 | CDK4/6 | Approved | |
| ERα (ESR1) | Estrogen receptor (ERα) | Approved | |
| Androgens | no target in corpus | — | |
| Aromatase | no target in corpus | — | |
| Co-activators, FOXA1 | no target in corpus | — | |
| Cyclin D1, MYC, PGR | no target in corpus | — | |
| ESR1 Y537S / D538G | no target in corpus | — | |
| Oestradiol | no target in corpus | — | |
| Proliferation | no target in corpus | — |
How drugs attack it, from the pathway page: Aromatase inhibitors (letrozole, anastrozole, exemestane) ± ovarian suppression; SERMs (tamoxifen); SERDs: fulvestrant, elacestrant, imlunestrant, camizestrant; PROTAC degrader vepdegestrant (2026); CDK4/6 inhibitors downstream; PI3K/AKT inhibitors for cross-talk.
SWI/SNF chromatin remodelling
A machine that opens and closes DNA so genes can be read. One in five cancers has a broken part (ARID1A, SMARCA4, PBRM1), and losing one part often creates a dependence on its twin, which is the basis for new synthetic-lethal drugs.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| PRC2 (EZH2) antagonism | EZH2 | Phase 3 | |
| SMARCB1 loss → EZH2 | EZH2 | Phase 3 | |
| ARID1A loss | no target in corpus | — | |
| BAF / PBAF / ncBAF | no target in corpus | — | |
| Enhancer access, differentiation genes | no target in corpus | — | |
| Nucleosome repositioning | no target in corpus | — | |
| SMARCA4 loss → SMARCA2 dependence | no target in corpus | — |
How drugs attack it, from the pathway page: SMARCA2 degraders (PRT3789, PRT7732) in SMARCA4-mutant cancers (phase 1/2); EZH2 inhibition in SMARCB1-deficient tumours (tazemetostat withdrawn 2026); ATR/PARP inhibitors in ARID1A-mutant tumours (trials); FHD-286 in AML.
VEGF angiogenesis
How tumours grow their own blood supply. Low oxygen makes cells release VEGF, which tells blood-vessel cells to sprout toward the tumour.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| HIF-1α / HIF-2α | HIF-2α | Approved | |
| VEGF-A | VEGF / VEGFR | Approved | |
| Angiogenesis, permeability | no target in corpus | — | |
| Hypoxia | no target in corpus | — | |
| Immune suppression (DC, Treg) | no target in corpus | — | |
| PLCγ / MAPK / PI3K | no target in corpus | — | |
| VEGFR2 (endothelium) | no target in corpus | — |
How drugs attack it, from the pathway page: Bevacizumab, ramucirumab (antibodies); VEGFR TKIs: axitinib, cabozantinib, lenvatinib, sunitinib; IO + VEGF combinations in RCC, HCC, endometrial cancer; PD-1×VEGF bispecifics: ivonescimab and successors; HIF-2α inhibitor belzutifan upstream in VHL-deficient RCC.
VHL / HIF oxygen sensing
The VHL/HIF pathway is how cells sense oxygen (the 2019 Nobel Prize). VHL destroys HIF when oxygen is present. Kidney cancers lose VHL, so HIF-2α is permanently on and drives blood vessel growth and proliferation.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| HIF-2α | HIF-2α | Approved | |
| VEGF, CAIX, GLUT1, cyclin D1 | VEGF / VEGFR | Approved | |
| Angiogenesis, glycolysis, growth | no target in corpus | — | |
| HIF-1β (ARNT) | no target in corpus | — | |
| Oxygen | no target in corpus | — | |
| PHD hydroxylases | no target in corpus | — | |
| VHL E3 ligase | no target in corpus | — |
How drugs attack it, from the pathway page: Belzutifan (HIF-2α) in VHL disease and RCC, adjuvant with pembrolizumab (2026); VEGF-directed therapy downstream; CAIX-targeted imaging (89Zr-girentuximab) and radioligands in development.
Androgen receptor signalling
Androgen receptor signalling is prostate cancer's engine. Testosterone becomes DHT, binds the androgen receptor, and drives growth genes. Castration removes the fuel; newer pills block the receptor or the enzyme that makes fuel inside the tumour.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Androgen receptor | Androgen receptor | Approved | |
| AR-V7 / amplification | no target in corpus | — | |
| CYP17A1 (adrenal/intratumoural) | no target in corpus | — | |
| DHT | no target in corpus | — | |
| GnRH → LH → testis | no target in corpus | — | |
| Proliferation | no target in corpus | — | |
| PSA, TMPRSS2-ERG, growth genes | no target in corpus | — | |
| Testosterone | no target in corpus | — |
How drugs attack it, from the pathway page: GnRH agonists/antagonists (leuprolide, relugolix); CYP17A1 inhibitor abiraterone; AR antagonists enzalutamide, apalutamide, darolutamide; PARP inhibitors + ARPI in HRR-mutant disease; capivasertib + abiraterone in PTEN-deficient; AR degraders, N-terminal domain inhibitors (trials).
Autophagy
Autophagy is the cell's recycling programme. Cancer cells, especially pancreatic and RAS-driven tumours, use it to survive starvation and drug stress, which is why hydroxychloroquine, an old malaria drug that blocks it, keeps appearing in trials.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Nutrient stress, KRAS/MEK inhibition | KRAS | Approved | |
| Autophagosome | no target in corpus | — | |
| Lysosome (HCQ blocks) | no target in corpus | — | |
| MHC-I degradation (PDAC) | no target in corpus | — | |
| mTORC1 (inhibits) | no target in corpus | — | |
| Recycled fuel → survival | no target in corpus | — | |
| ULK1 / AMPK | no target in corpus | — |
How drugs attack it, from the pathway page: Hydroxychloroquine + MEK inhibitor or + KRAS inhibitor in PDAC (phase 1/2); ULK1 inhibitors (DCC-3116) in RAS-driven cancers; Autophagy inhibition to restore MHC-I and immunotherapy response (preclinical).
B-cell receptor / BTK signalling (to NF-κB)
The B-cell receptor is the survival switch of B cells. Signals from it pass through BTK to free NF-kappa-B, which keeps the cell alive. B-cell cancers hold it on; BTK inhibitors, proteasome inhibitors and lenalidomide each cut the line at a different point.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| BCL2, IL-6, IL-10, cyclin D → survival | BCL-2 | Approved | |
| B-cell receptor / antigen | no target in corpus | — | |
| CARD11 / BCL10 / MALT1 | no target in corpus | — | |
| IKK complex | no target in corpus | — | |
| IRF4 / IKZF1-3 (lenalidomide) | no target in corpus | — | |
| IκB (destroyed by proteasome) | no target in corpus | — | |
| NF-κB (p65 / p50) | no target in corpus | — | |
| SYK → BTK → PLCγ2 | no target in corpus | — | |
| TLR → MYD88 (L265P) | no target in corpus | — |
How drugs attack it, from the pathway page: Covalent BTK inhibitors ibrutinib, acalabrutinib, zanubrutinib; non-covalent pirtobrutinib after BTK C481S resistance; BTK degraders in trials; Proteasome inhibitors bortezomib, carfilzomib and ixazomib block IκB degradation in multiple myeloma and mantle cell lymphoma; Lenalidomide and the CELMoDs degrade IKZF1/3, cutting IRF4 and NF-κB output; BCL2 inhibition (venetoclax) removes the main survival gene NF-κB switches on.
Cancer metabolism
Cancer cells rewire how they eat. They burn glucose inefficiently but fast (the Warburg effect), gorge on glutamine and fats, and build the nucleotides and lipids needed to divide. This is why the FDG PET scan works, and why metabolism is a drug target.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Mutant IDH → 2-HG | IDH1 / IDH2 | Approved | |
| Aerobic glycolysis (Warburg) | no target in corpus | — | |
| De novo lipogenesis (FASN) | no target in corpus | — | |
| Glucose (GLUT1) | no target in corpus | — | |
| Glutamine → glutaminase | no target in corpus | — | |
| Lactate export (MCT4) | no target in corpus | — | |
| One-carbon (SHMT2, MTHFD2) → nucleotides | no target in corpus | — | |
| PI3K/AKT/mTOR, MYC, HIF | no target in corpus | — | |
| TCA cycle | no target in corpus | — |
How drugs attack it, from the pathway page: Antimetabolite chemotherapy (5-FU, gemcitabine, methotrexate) exploits nucleotide demand; IDH inhibitors (ivosidenib, vorasidenib) block 2-HG; Glutaminase, MCT1, FASN, and arginine-deprivation agents in trials; FDG PET images the Warburg effect; Diet and metformin trials as adjuncts.
CD47 / SIRPα (the 'don't eat me' signal)
Macrophages eat cells that look wrong, unless the cell shows CD47, a 'don't eat me' badge. Many cancers overproduce CD47 to escape being eaten. Antibodies that cover the badge should let macrophages clear the tumour; the idea works in the lab, but the leading drug failed in blood cancers because red cells wear the same badge.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| CD47 on tumour (and red) cells | CD47 | ||
| Antigen presentation → T-cell priming | no target in corpus | — | |
| Phagocytosis of the tumour cell | no target in corpus | — | |
| Pro-phagocytic signals: calreticulin, antibody Fc (rituximab) | no target in corpus | — | |
| Red cells (on-target anaemia) | no target in corpus | — | |
| SHP-1 / SHP-2 | no target in corpus | — | |
| SIRPα on macrophage | no target in corpus | — |
How drugs attack it, from the pathway page: Anti-CD47 magrolimab with azacitidine: phase 3 ENHANCE, ENHANCE-2 and ENHANCE-3 stopped for futility or harm; programme discontinued (2024); SIRPα-Fc fusions (evorpacept) and Fc-silent or low-affinity anti-CD47 antibodies designed to spare red cells; CD47 × CD19 or CD20 bispecifics to confine blockade to B-cell tumours; Combination with opsonising antibodies (rituximab, cetuximab, trastuzumab) to supply the 'eat me' signal.
Clonal evolution & minimal residual disease
A tumour is a population that evolves by natural selection. Treatment kills the sensitive cells and selects the rest, which is why resistance is the rule; measuring the surviving population (MRD) and adapting therapy is the counter-strategy.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Truncal driver clone | TP53 | Approved | |
| Adaptive / combination therapy | no target in corpus | — | |
| MRD (ctDNA) | no target in corpus | — | |
| Relapse dominated by B | no target in corpus | — | |
| Subclone A | no target in corpus | — | |
| Subclone B (resistant) | no target in corpus | — | |
| Therapy (selection) | no target in corpus | — |
How drugs attack it, from the pathway page: ctDNA MRD to escalate or de-escalate (IMvigor011, DYNAMIC); Upfront combinations to pre-empt resistant clones (osimertinib + chemotherapy, BRAF + MEK); Adaptive therapy trials (Moffitt); Serial liquid biopsy to switch therapy at molecular progression (SERENA-6).
Clonal haematopoiesis (CHIP)
As we age, blood stem cells with cancer-like mutations quietly expand in most people. These clones raise leukaemia and heart disease risk, are accelerated by chemotherapy, and confuse blood tests for cancer DNA.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| DNMT3A, TET2, ASXL1, PPM1D, TP53 | TP53 | Approved | |
| Ageing HSCs | no target in corpus | — | |
| Chemo, PARPi, radioligands select | no target in corpus | — | |
| CHIP clone (VAF ≥2%) | no target in corpus | — | |
| False-positive ctDNA | no target in corpus | — | |
| Inflammation → cardiovascular disease | no target in corpus | — | |
| Therapy-related MDS/AML | no target in corpus | — |
How drugs attack it, from the pathway page: Paired white-blood-cell sequencing in liquid biopsy pipelines; Monitoring after PARP inhibitors and radioligand therapy; IL-1β/IL-6 blockade trials for CHIP-associated cardiovascular risk.
Ferroptosis & regulated cell death
Cells can die in several programmed ways. Beyond the classic apoptosis, ferroptosis kills through iron-driven fat oxidation, and drug-resistant, mesenchymal cancer cells turn out to be unusually prone to it.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Apoptosis (BCL-2 family) | BCL-2 | Approved | |
| Cystine import (SLC7A11) | no target in corpus | — | |
| Ferroptosis | no target in corpus | — | |
| Glutathione | no target in corpus | — | |
| GPX4 | no target in corpus | — | |
| Labile iron (Fenton) | no target in corpus | — | |
| Lipid peroxidation | no target in corpus | — | |
| Mesenchymal / persister state | no target in corpus | — |
How drugs attack it, from the pathway page: xCT inhibitors, cyst(e)inase, sulfasalazine repurposing (early trials); Radiotherapy and IFN-γ from T cells induce lipid peroxidation; BH3 mimetics (venetoclax) exploit apoptosis; MCL-1 inhibitors in development; Persister-cell targeting after EGFR/ALK inhibitors (preclinical).
Field cancerisation
Cancer often arises from a whole region of tissue that already carries mutations, not from one rogue cell. Sun-exposed skin, smokers' airways, and Barrett's oesophagus are patchworks of mutant clones competing long before a tumour appears.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Mutant clones in normal tissue (NOTCH1, TP53) | TP53 | Approved | |
| Carcinogen exposure, ageing | no target in corpus | — | |
| Clonal competition | no target in corpus | — | |
| Interception: chemoprevention, ablation | no target in corpus | — | |
| Progression to dysplasia → cancer | no target in corpus | — | |
| Second primaries, local recurrence | no target in corpus | — |
How drugs attack it, from the pathway page: Surveillance and ablation of precancer (Barrett's RFA, cervical precancer ablation, colon polypectomy); Chemoprevention (aspirin in Lynch, tamoxifen, HPV vaccination); Field-directed therapy after resection (e.g., 5-FU cream for actinic keratosis); Molecular monitoring of fields (cytosponge, sputum, urine).
Inflammation & NF-κB
Chronic inflammation is soil for cancer: it feeds growth signals, DNA damage, and immune suppression. The NF-κB switch inside cells is the master relay, and colitis, hepatitis, and H. pylori gastritis are the clinical proof.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| BCR → BTK (lymphoma) | BTK (Bruton tyrosine kinase) | Approved | |
| COX-2 → PGE2 | no target in corpus | — | |
| IKK → IκB degradation | no target in corpus | — | |
| IL-6 → STAT3 | no target in corpus | — | |
| Infection, injury, obesity | no target in corpus | — | |
| NF-κB | no target in corpus | — | |
| Survival, proliferation, SASP, immune suppression | no target in corpus | — | |
| TNF, IL-1β, IL-6 | no target in corpus | — |
How drugs attack it, from the pathway page: Aspirin chemoprevention in Lynch syndrome (CAPP2); NSAIDs in FAP; BTK inhibitors (ibrutinib, zanubrutinib) shut NF-κB in CLL/lymphoma; IL-6/STAT3 blockade in cachexia and CRS (tocilizumab); Anti-H. pylori therapy prevents gastric cancer; HBV/HCV treatment prevents HCC.
Intrinsic apoptosis (BCL-2 family)
Intrinsic apoptosis is the cell's self-destruct switch. BCL-2 holds it shut; BAX and BAK pull it open. Venetoclax pries BCL-2 off so the switch can fire.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| BCL-2 / BCL-XL / MCL-1 | BCL-2 | Approved | |
| BAX / BAK | no target in corpus | — | |
| BH3-only (BIM, PUMA, NOXA) | no target in corpus | — | |
| Caspase-3/7 → apoptosis | no target in corpus | — | |
| Cytochrome c → caspase-9 | no target in corpus | — | |
| DNA damage, oncogene stress, p53 | no target in corpus | — | |
| Mitochondrial permeabilisation | no target in corpus | — |
How drugs attack it, from the pathway page: Venetoclax (BCL-2) in CLL, AML, mantle cell lymphoma; Next-generation BCL-2 inhibitors sonrotoclax, lisaftoclax; MCL-1 inhibitors (limited by cardiotoxicity); BCL-XL PROTACs sparing platelets; Combinations with hypomethylating agents, BTK inhibitors, menin inhibitors.
Invasion: proteases, adhesion & the invasive front
To invade, a cancer cell must grip the scaffolding around it, dissolve a path with enzymes, and pull itself forward, alone or in a chain led by a scout cell. Fibroblasts often cut the trail first. The enzyme blockers of the 1990s failed; today's targets are the grip (integrins, FAK) and the trail-makers.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| CAF tracks | FAP | Phase 2 | |
| Amoeboid squeezing | no target in corpus | — | |
| Collective invasion (leaders) | no target in corpus | — | |
| EMT programme (ZEB1, SNAIL) | no target in corpus | — | |
| Integrins → FAK / SRC | no target in corpus | — | |
| Invadopodia, MT1-MMP | no target in corpus | — | |
| Invasive front → vessels | no target in corpus | — | |
| MMP2/9, uPA → ECM breach | no target in corpus | — | |
| RHO–ROCK contraction | no target in corpus | — | |
| TGF-β, HGF, hypoxia, stiffness | no target in corpus | — |
How drugs attack it, from the pathway page: FAK inhibitor defactinib with avutometinib (approved 2025, KRAS-mutant low-grade serous ovarian cancer); FAK inhibition also softens stroma; Broad MMP inhibitors and the integrin antagonist cilengitide failed in phase 3; lesson retained in the failure museum; Surgery and radiotherapy margins are the practical answer to local invasion; perineural and lymphovascular invasion drive adjuvant decisions; Anti-stromal strategies (FAP theranostics, Hedgehog paradox) reshape the tracks.
JAK–STAT signalling
The relay that turns cytokine signals into gene changes. Overactive in blood cancers (JAK2 in myelofibrosis), it is also the wire that carries interferon's cancer-killing message, so tumours cut it to escape immunotherapy.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| MHC-I, PD-L1 (STAT1) | PD-L1 | Approved | |
| Cytokine / IFN-γ | no target in corpus | — | |
| JAK1/2 | no target in corpus | — | |
| Receptor | no target in corpus | — | |
| SOCS feedback | no target in corpus | — | |
| STAT1 / STAT3 / STAT5 | no target in corpus | — | |
| Survival, SASP, cachexia (STAT3) | no target in corpus | — |
How drugs attack it, from the pathway page: JAK inhibitors in myeloproliferative neoplasms and GVHD; STAT3 degraders/antisense (early trials); Anti-IL-6 (tocilizumab) for CRS and under study for cachexia; JAK-loss tumours: MHC-independent therapies (T-cell engagers, NK cells).
Microbiome–tumour interactions
The bacteria in the gut, and even inside tumours, influence whether cancer starts and whether immunotherapy works. Transplanting stool from responders has made some non-responders respond.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Immunotherapy response | PD-1 | Approved | |
| Antibiotics | no target in corpus | — | |
| Chemotherapy degradation, inflammation | no target in corpus | — | |
| Colibactin → mutational signature | no target in corpus | — | |
| Dendritic / T-cell priming | no target in corpus | — | |
| Gut microbiota | no target in corpus | — | |
| Intratumoural bacteria | no target in corpus | — | |
| Metabolites (SCFA, inosine, bile acids) | no target in corpus | — |
How drugs attack it, from the pathway page: FMT from responders with PD-1 blockade (phase 2); Defined bacterial consortia (VE800, SER-155) and diet (fibre) trials; Antibiotic stewardship around immunotherapy; Fusobacterium-targeted strategies (research).
mRNA translation (eIF4F / mTOR)
Cancer cells must make protein at furious speed. The eIF4F complex that starts protein synthesis is the funnel where growth signals converge, and drugs that pinch the funnel starve the tumour of the proteins it needs most.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| mTORC1 | AKT | Approved | |
| 4E-BP | no target in corpus | — | |
| eIF4E | no target in corpus | — | |
| eIF4F (4E/4G/4A) | no target in corpus | — | |
| MNK1/2 | no target in corpus | — | |
| MYC, cyclin D1, MCL-1 translation | no target in corpus | — | |
| Ribosome biogenesis (Pol I) | no target in corpus | — |
How drugs attack it, from the pathway page: mTOR inhibitors (everolimus) approved in breast, RCC, NET; eIF4A inhibitor zotatifin (eFT226) phase 1/2 with fulvestrant/abemaciclib; MNK inhibitors (tomivosertib) in NSCLC (mixed); RNA Pol I inhibitors (CX-5461, pidnarulex) in HRD cancers.
Mutagenesis & mutational signatures
Every cause of DNA damage leaves its own fingerprint in the genome: sunlight, tobacco, a faulty repair enzyme, a gut bacterium. Reading these fingerprints tells you what caused a cancer and which repair crews it is missing, which in turn predicts which drugs will work.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Repair: MMR, HR, BER, NER | BRCA1 / BRCA2 (HRD) | Approved | |
| DNA lesions | no target in corpus | — | |
| Drivers, neoantigens | no target in corpus | — | |
| Endogenous: APOBEC, ROS | no target in corpus | — | |
| Exogenous: UV, tobacco | no target in corpus | — | |
| Fixed mutations | no target in corpus | — | |
| HRD, MSI, TMB biomarkers | no target in corpus | — | |
| Replication errors | no target in corpus | — | |
| Signature (SBS, ID, CN) | no target in corpus | — |
How drugs attack it, from the pathway page: Prevention removes the mutagen: smoking cessation, UV protection, HPV/HBV vaccination, aflatoxin control; HRD signatures select PARP inhibitors and platinum; MSI/TMB select checkpoint inhibitors; Signature-aware design: avoid TMZ in MGMT-unmethylated tumours, expect APOBEC-driven resistance; Whole-genome sequencing and methylation profiling read the fingerprints.
Mutant IDH / 2-hydroxyglutarate
A single mutation in a metabolic enzyme (IDH1 or IDH2) makes cells pour out a molecule they should never make, 2-hydroxyglutarate. It jams the machinery that erases chemical marks on DNA and histones, so blood and brain cells get stuck before they mature. Pills that block the mutant enzyme let them mature again.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Mutant IDH1 / IDH2 (R132, R140, R172) | IDH1 / IDH2 | Approved | |
| 2-hydroxyglutarate (oncometabolite) | no target in corpus | — | |
| Differentiation block → leukaemia, glioma | no target in corpus | — | |
| DNA and histone hypermethylation (G-CIMP) | no target in corpus | — | |
| JmjC histone demethylases | no target in corpus | — | |
| TET2 DNA demethylase | no target in corpus | — | |
| α-ketoglutarate | no target in corpus | — |
How drugs attack it, from the pathway page: Ivosidenib (IDH1) for relapsed AML, first-line AML with azacitidine (AGILE), IDH1-mutant cholangiocarcinoma and MDS; Olutasidenib (IDH1) and enasidenib (IDH2) for relapsed or refractory AML; Vorasidenib (dual IDH1/2, brain-penetrant) for residual or recurrent grade 2 IDH-mutant astrocytoma and oligodendroglioma (INDIGO); Differentiation syndrome is the class toxicity; steroids and hydroxyurea manage it; Combination with venetoclax and azacitidine, and with PARP inhibitors (2-HG induces a homologous-recombination defect), under study.
MYC
MYC is the most commonly amplified cancer gene, a master switch that turns on thousands of growth genes. It has no pocket for a conventional drug, so it remained 'undruggable' for 40 years; the first direct MYC drugs finally entered trials in the 2020s.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| CD47, PD-L1 (immune evasion) | CD47 | ||
| AURKA / PLK1 (stability) | no target in corpus | — | |
| CDK9 / BET (transcription) | no target in corpus | — | |
| MYC/MAX | no target in corpus | — | |
| Proliferation | no target in corpus | — | |
| Ribosome biogenesis, metabolism | no target in corpus | — | |
| Wnt, RAS, Notch, amplification | no target in corpus | — |
How drugs attack it, from the pathway page: OMO-103 (Omomyc) phase 1/2 in pancreatic cancer; BET and CDK9 inhibitors reduce MYC transcription (haematologic trials); AURKA inhibitors in MYCN-amplified neuroblastoma; MYC-driven dependencies: mTOR, spliceosome, glutamine.
Notch signalling
A cell-to-cell contact signal that decides cell fate. It drives T-cell leukaemia when mutated on, acts as a tumour suppressor in some squamous cancers when lost, and its ligand DLL3 became a drug target in small-cell lung cancer.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| DLL3 (inhibitory; SCLC surface) | DLL3 | Approved | |
| DLL/JAG ligand (neighbour) | no target in corpus | — | |
| HES1/HEY, MYC | no target in corpus | — | |
| NICD → RBPJ | no target in corpus | — | |
| NOTCH receptor | no target in corpus | — | |
| γ-secretase cleavage | no target in corpus | — |
How drugs attack it, from the pathway page: Nirogacestat (γ-secretase inhibitor) in desmoid tumours; DLL3-directed tarlatamab in SCLC; DLL3 ADCs and trispecifics; NOTCH1-mutant CLL: reduced benefit from anti-CD20, informs regimen choice.
RNA splicing
Genes are cut and pasted into messages before they are used. Blood cancers often carry mutations in the splicing machinery, and the errors create abnormal proteins that could serve as targets or immune flags.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Aberrant isoforms (AR-V7) | Androgen receptor | Approved | |
| Pre-mRNA | no target in corpus | — | |
| PRMT5 dependence | no target in corpus | — | |
| R-loops, replication stress | no target in corpus | — | |
| SF3B1 / SRSF2 / U2AF1 (mutant) | no target in corpus | — | |
| Splice neoantigens | no target in corpus | — | |
| Spliceosome | no target in corpus | — |
How drugs attack it, from the pathway page: Spliceosome modulators (H3B-8800 negative; next generation in development); PRMT5 inhibitors in MTAP-deleted and splicing-mutant cancers; Antisense oligonucleotides to redirect splicing (AR-V7, BCL2L1); Splice-derived neoantigen vaccines (research).
The blood–brain barrier & brain metastasis
The brain's blood vessels are sealed tight and fitted with pumps that eject most drugs. That protects the brain from poisons but also from chemotherapy and antibodies. Cancer cells that do squeeze through recruit the brain's own support cells, astrocytes, to feed and shield them.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Brain-penetrant TKIs, FUS | HER2 | Approved | |
| Astrocytes: Cx43, cGAMP | no target in corpus | — | |
| BBB: tight junctions, pericytes | no target in corpus | — | |
| Brain metastasis | no target in corpus | — | |
| CTC arrest at capillary | no target in corpus | — | |
| Drugs excluded | no target in corpus | — | |
| Extravasation (cathepsin S) | no target in corpus | — | |
| P-gp / BCRP efflux | no target in corpus | — | |
| Vascular co-option (L1CAM) | no target in corpus | — |
How drugs attack it, from the pathway page: Brain-penetrant TKIs: osimertinib (EGFR), lorlatinib/alectinib (ALK), tucatinib (HER2, HER2CLIMB), plus T-DXd intracranial activity; Radiosurgery and hippocampal-sparing whole-brain RT; prophylactic cranial irradiation vs MRI surveillance in SCLC; Focused ultrasound BBB opening, LITT, intrathecal and intraventricular delivery for leptomeningeal disease; Astrocyte gap-junction (meclofenamate, tonabersat) and STING-axis blockade in trials.
Basement membrane & tissue barriers
Every organ keeps its lining cells behind a thin, dense sheet of protein called the basement membrane. A tumour that has not crossed it is 'in situ' and essentially curable; crossing it is the moment cancer becomes invasive.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Basement membrane | no target in corpus | — | |
| Carcinoma in situ | no target in corpus | — | |
| E-cadherin junctions | no target in corpus | — | |
| Integrins / hemidesmosomes | no target in corpus | — | |
| Invasive carcinoma | no target in corpus | — | |
| MMPs, uPA, invadopodia | no target in corpus | — | |
| Myoepithelial layer | no target in corpus | — | |
| Polarised epithelium | no target in corpus | — | |
| Stroma, vessels | no target in corpus | — |
How drugs attack it, from the pathway page: Screening and excision of in situ disease (colposcopy, DCIS surgery, endoscopic resection) before the breach; HPV vaccination removes the commonest driver of cervical in situ lesions; MMP inhibitors failed clinically in the 1990s; invasion is now approached via FAK, integrin and stromal targets; Staging (Tis vs T1) and margins encode whether the barrier was crossed.
Cancer cachexia
The wasting syndrome that kills up to a third of cancer patients: tumours send hormonal signals (GDF-15, IL-6) that switch off appetite and burn muscle and fat. The first drug to reverse it, ponsegromab, showed weight gain in 2024.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Anorexia | no target in corpus | — | |
| GDF-15 → GFRAL (brainstem) | no target in corpus | — | |
| IL-6 / TNF / activin | no target in corpus | — | |
| Muscle proteolysis, fat lipolysis | no target in corpus | — | |
| Tumour + inflammation | no target in corpus | — | |
| Weight loss, frailty, death | no target in corpus | — |
How drugs attack it, from the pathway page: Ponsegromab (anti-GDF-15) phase 3; Anamorelin (approved Japan), olanzapine for appetite, corticosteroids short term; Exercise and nutrition support (ESPEN/ASCO guidelines); Anti-IL-6 and activin/myostatin agents in trials.
Cancer neuroscience (nerve–tumour signalling)
Cancer neuroscience is the study of how tumours talk to nerves. Nerves grow into tumours and feed them signals; brain tumours even wire themselves into neural circuits. Cutting the conversation with common drugs such as beta-blockers is now being tested.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Growth, invasion, immunosuppression | no target in corpus | — | |
| Nerve ingrowth (PNI) | no target in corpus | — | |
| Neuron–glioma synapses (AMPA) | no target in corpus | — | |
| NGF, axon guidance cues | no target in corpus | — | |
| Tumour | no target in corpus | — | |
| β-adrenergic / cholinergic signals | no target in corpus | — |
How drugs attack it, from the pathway page: Propranolol and other β-blockers in trials (melanoma, breast, angiosarcoma); Botulinum toxin denervation trials (gastric); NGF/TrkA and AMPA-receptor (perampanel) blockade; gabapentin in glioma trials; Perineural invasion as a staging biomarker.
cGAS–STING innate sensing
cGAS-STING is the cell's alarm for DNA in the wrong place. Radiation, chemotherapy, and ADCs spill DNA into the cytoplasm; cGAS detects it, STING sounds the alarm, and interferon calls in the immune system.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| cGAMP | no target in corpus | — | |
| cGAS | no target in corpus | — | |
| Cytosolic dsDNA / micronuclei | no target in corpus | — | |
| ENPP1 | no target in corpus | — | |
| Radiation, chemo, ADC payload | no target in corpus | — | |
| STING | no target in corpus | — | |
| TBK1 → IRF3 / NF-κB | no target in corpus | — | |
| Type I IFN, CXCL10 → T-cell recruitment | no target in corpus | — |
How drugs attack it, from the pathway page: Radiotherapy (especially hypofractionated) + checkpoint inhibitors; PARP inhibitor + PD-1 combinations; STING agonists (intratumoural, systemic, antibody-conjugated); ENPP1 inhibitors; TOP1-payload ADCs + IO (ASCENT-04, EV-302 analogues).
Epithelial–mesenchymal transition & drug efflux
How a cancer cell changes shape to migrate and to shrug off drugs. Transcription factors like ZEB1 and SNAIL loosen the cell, switch on pumps that eject chemotherapy, and hide it from the immune system.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| ABCB1 / ABCG2 efflux | no target in corpus | — | |
| E-cadherin, claudins | no target in corpus | — | |
| Immune exclusion | no target in corpus | — | |
| Invasion, metastasis, drug resistance | no target in corpus | — | |
| Stemness, apoptosis resistance | no target in corpus | — | |
| TGF-β, Wnt, Notch, hypoxia | no target in corpus | — | |
| Vimentin, N-cadherin, MMPs | no target in corpus | — | |
| ZEB1/2, SNAIL, TWIST | no target in corpus | — |
How drugs attack it, from the pathway page: No approved direct EMT inhibitor; Payloads with low efflux susceptibility (sac-TMT's belotecan derivative claims this) and radiation (efflux-independent); TGF-β pathway blockade (mostly failed so far); Ferroptosis inducers for mesenchymal-state cells (preclinical); Immune approaches to overcome exclusion (STING, radiation).
Hedgehog signalling
A developmental pathway that shapes embryos and is switched back on in basal cell skin cancer and some brain tumours. Blocking it cures most advanced basal cell carcinomas, but tumours learn to reactivate it downstream.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| GLI1/2 | no target in corpus | — | |
| Proliferation (BCC, SHH-medulloblastoma) | no target in corpus | — | |
| PTCH1 | no target in corpus | — | |
| SHH ligand | no target in corpus | — | |
| SMO | no target in corpus | — | |
| SUFU | no target in corpus | — |
How drugs attack it, from the pathway page: SMO inhibitors vismodegib, sonidegib (advanced BCC), glasdegib (AML); GLI inhibitors (arsenic trioxide, BET inhibitors) for downstream resistance (investigational); Surgery and radiation remain first line for most BCC.
Hippo–YAP/TAZ
The pathway that tells organs when to stop growing. Cancers disable it so YAP and TAZ stay in the nucleus driving growth; in mesothelioma, NF2 loss does exactly that, and the first drugs against the YAP–TEAD switch are in trials.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Contact, stiffness, GPCRs | no target in corpus | — | |
| Growth, EMT, drug tolerance | no target in corpus | — | |
| MST1/2 → LATS1/2 | no target in corpus | — | |
| NF2 (Merlin) | no target in corpus | — | |
| TEAD transcription | no target in corpus | — | |
| YAP/TAZ | no target in corpus | — |
How drugs attack it, from the pathway page: TEAD inhibitors (VT3989, IK-930, IAG933) in NF2-mutant mesothelioma and with KRAS/EGFR inhibitors; Verteporfin repurposing (preclinical); Combination rationale: YAP bypass after MAPK inhibition.
KEAP1–NRF2 antioxidant pathway
KEAP1–NRF2 is the cell's antioxidant defence switch. Lung cancers often break the off-switch (KEAP1), leaving NRF2 permanently on, which detoxifies chemotherapy and radiation and makes these tumours resistant to almost everything.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| ARE genes: GSH, NQO1, efflux | no target in corpus | — | |
| Chemo/RT/ferroptosis resistance | no target in corpus | — | |
| KEAP1 (mutated) | no target in corpus | — | |
| NRF2 | no target in corpus | — | |
| Oxidative stress | no target in corpus | — | |
| STK11/LKB1 loss (co-mutation) | no target in corpus | — |
How drugs attack it, from the pathway page: Glutaminase inhibition (negative in KEAPSAKE); NRF2-activated prodrugs and NRF2 inhibitors (preclinical); Biomarker: KEAP1/STK11 status predicts poor IO benefit in NSCLC; CDK4/6 and mTOR combinations under study.
Organ tropism: seed and soil
Breast cancer goes to bone, lung, liver and brain; prostate cancer to bone; colon cancer to liver; uveal melanoma almost only to liver. Paget's 1889 idea still holds: where a cancer spreads depends on both the seed (the cell's programme) and the soil (the organ's welcome). Each soil has its own vicious cycle, and some are druggable.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Blood-flow anatomy | no target in corpus | — | |
| Bone: RANKL vicious cycle | no target in corpus | — | |
| Brain: astrocytes, BBB | no target in corpus | — | |
| CTC (seed programme) | no target in corpus | — | |
| Denosumab, radium-223 | no target in corpus | — | |
| Liver: Kupffer, stellate cells | no target in corpus | — | |
| Lung: tenascin C, periostin | no target in corpus | — | |
| Organ-specific colonisation | no target in corpus | — | |
| SBRT, HIPEC, TARE | no target in corpus | — | |
| TGF-β, IGF-1 released | no target in corpus | — |
How drugs attack it, from the pathway page: Bone: denosumab and zoledronic acid break the vicious cycle; radium-223 and 177Lu-PSMA in bone-predominant prostate cancer; Brain-penetrant TKIs and surveillance MRI in HER2+ breast, ALK+ lung and SCLC; Regional therapy for organ-confined spread: HIPEC (peritoneum), radioembolisation and liver transplant (liver), SBRT for oligometastases; Tropism-aware adjuvant trials and exosome profiling to predict relapse site.
TGF-β signalling
A signal that stops normal cells from dividing but, once a cancer is established, switches sides: it builds scar-like stroma, walls out immune cells, and pushes cells into a migratory state.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Cytostasis (early) | no target in corpus | — | |
| EMT, CAF activation | no target in corpus | — | |
| Latent TGF-β (activated by integrins) | no target in corpus | — | |
| SMAD2/3–SMAD4 | no target in corpus | — | |
| SMAD4 loss (PDAC) | no target in corpus | — | |
| T-cell exclusion | no target in corpus | — | |
| TGFBR2 / ALK5 | no target in corpus | — |
How drugs attack it, from the pathway page: TGF-β traps and antibodies (mostly failed: bintrafusp alfa); latent-TGF-β1-selective agents in trials; ALK5 inhibitors (vactosertib) with IO in trials; Integrin αvβ6/αvβ8 blockade to prevent activation (investigational).
The metastatic cascade
How cancer spreads: cells leave the tumour, squeeze into blood or lymph vessels, survive the journey, exit into a new organ, often sleep there for years, and finally grow. Metastasis causes about 90% of cancer deaths.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Colonisation / macrometastasis | no target in corpus | — | |
| CTCs in circulation | no target in corpus | — | |
| DTC dormancy | no target in corpus | — | |
| Extravasation | no target in corpus | — | |
| Intravasation | no target in corpus | — | |
| Invasion (EMT, MMPs) | no target in corpus | — | |
| NK / T-cell clearance | no target in corpus | — | |
| Pre-metastatic niche (exosomes, myeloid cells) | no target in corpus | — | |
| Primary tumour | no target in corpus | — |
How drugs attack it, from the pathway page: Adjuvant systemic therapy and ctDNA-guided escalation aim at DTCs before colonisation; Anti-EMT and anti-MMP drugs failed historically; TGF-β blockade is being retried in combinations; Dormancy-maintaining strategies (see tumour dormancy) are the newest idea; Metastasis-directed SBRT for oligometastatic disease.
Tumour dormancy
Cancer cells can hide in bone marrow, lung, or brain for years or decades, asleep and invisible to scans and chemotherapy, then wake up. Late relapse in breast and prostate cancer is dormancy ending.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Awakening: NETs, inflammation, ageing | no target in corpus | — | |
| Disseminated tumour cell | no target in corpus | — | |
| Late relapse | no target in corpus | — | |
| Niche: TGF-β2, BMP7, endothelium | no target in corpus | — | |
| NK / T-cell surveillance | no target in corpus | — | |
| Quiescence (p38↑, ERK↓, NR2F1) | no target in corpus | — |
How drugs attack it, from the pathway page: Extended adjuvant endocrine therapy and CDK4/6 inhibitors (de facto dormancy maintenance); 5-azacytidine + all-trans retinoic acid to enforce dormancy (pilot, prostate); MRD-guided intervention at molecular relapse; NET/inflammation inhibitors to prevent awakening (preclinical).
Wnt / β-catenin
Wnt/β-catenin is a developmental pathway hijacked by colorectal cancer. Normally a destruction complex keeps β-catenin low; losing APC lets it flood the nucleus and drive growth genes.
| Node | Target | Products hitting the node | Best phase |
|---|---|---|---|
| Destruction complex (APC, AXIN, GSK3β) | no target in corpus | — | |
| Frizzled / LRP5/6 | no target in corpus | — | |
| MYC, cyclin D1, LGR5 | no target in corpus | — | |
| RNF43 / RSPO | no target in corpus | — | |
| TCF/LEF | no target in corpus | — | |
| Wnt ligand | no target in corpus | — | |
| β-catenin | no target in corpus | — |
How drugs attack it, from the pathway page: Porcupine inhibitors (RSPO-fusion / RNF43-mutant tumours, trials); Gamma-secretase inhibitor nirogacestat in desmoid tumours (approved 2023); Tankyrase inhibitors (preclinical/early); Indirect: chemoprevention with aspirin/COX-2 in Lynch and FAP.
A node counts as drugged when a product in the corpus lists its target; a druggable node with no drug means no product in OnCo names that target, not that none exists anywhere. Nodes without a target id are pathway components (ligands, complexes, processes) that have no target page yet.