DNA repair pathways and synthetic lethality
Double-strand breaks (HR versus end joining), copying errors (mismatch repair), and single damaged letters (base excision, PARP) each have their crew. Tumours that lost one crew survive on the others, and that dependence is the first widely successful way to drug a lost gene.
Diagram
Pick a product above a diagram to see the nodes it hits and the escape routes below the block. Hover or tap any node or arrow for what it is; every node opens its target, glossary entry or the pathway page. Violet boxes are druggable targets.
A torn page. The careful archivist (HR) fetches the twin copy from the shelf and transcribes it letter for letter; the hurried clerk (NHEJ) tapes the two halves together, losing a few words. Tumours missing the archivist survive on the clerk, so anything that adds more torn pages (PARP inhibitors, platinum, radiation) buries them.
A spell-checker that runs after every page is typed. Without it, typos pile up, especially in words like 'banana' where it is easy to lose count of the repeats. The garbled words in the resulting proteins read as foreign, so the immune system, once its brakes are released, attacks with unusual vigour.
Potholes on a busy road. Normally a small crew fills them overnight and PARP is the foreman who cones them off. A PARP inhibitor glues the foreman to the pothole; in the morning the traffic (replication) hits him and the road collapses, and only the bridge-building crew (BRCA) could rebuild it.
What happens
In plain words, then the glossary entries the stage rests on. Chapter 4, Evading death and repair: To survive the damage they generate and the treatments thrown at them, cancer cells rewire death and repair.
Double-strand breaks (HR versus end joining), copying errors (mismatch repair), and single damaged letters (base excision, PARP) each have their crew. Tumours that lost one crew survive on the others, and that dependence is the first widely successful way to drug a lost gene.
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.
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.
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.
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.
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.
The molecular players
The proteins and genes at this stage, with their role and how many products act on each. Listed players come from the atlas; drawn players sit as nodes in the diagrams above.
PARP is a DNA repair enzyme. Cancers that have already lost one repair system (BRCA) die when this second one is blocked; healthy cells survive.
DNA repair genes. Inheriting a broken copy raises breast and ovarian cancer risk, but tumours that lose them become uniquely vulnerable to PARP inhibitors and platinum.
An enzyme that cancers lacking the MTAP gene (about 10-15% of all tumours) depend on more than normal cells do; new inhibitors designed to exploit that difference are in late trials.
ATR is a DNA-damage alarm kinase. Blocking it makes tumours with broken repair systems collapse under their own replication stress.
A checkpoint kinase that gives cells time to fix DNA before dividing. Removing it forces damaged cancer cells into a fatal division.
A DNA-unwinding enzyme that mismatch-repair-deficient cancers cannot live without; the first WRN inhibitors are in trials as a chemotherapy-free option for MSI-high tumours that fail immunotherapy.
PD-1 is a brake on T cells. Blocking it releases the immune system against the tumour and has cured some previously incurable cancers.
TP53 is the 'guardian of the genome', broken in half of all cancers. Fixing it directly has so far defeated every attempt, so drugs exploit what its loss makes cancers depend on.
Where medicines act
Products grouped by the node they hit, most advanced first, with the cancers an approved product is linked to. Pick one above the diagram to see it light up.
- NiraparibApprovedOvarian cancerProstate cancerHigh-grade serous ovarian cancer
- OlaparibApprovedOvarian cancerTriple-negative breast cancer (TNBC)HR-positive / HER2-negative breast cancer
- RucaparibApprovedOvarian cancerProstate cancerHigh-grade serous ovarian cancer
- TalazoparibApprovedTriple-negative breast cancer (TNBC)HR-positive / HER2-negative breast cancerProstate cancer
- BRACAnalysis CDxApprovedOvarian cancerHR-positive / HER2-negative breast cancerTriple-negative breast cancer (TNBC)
- myChoice CDxApprovedOvarian cancer
- SaruparibPhase 3
- PalacaparibPhase 2
- +1 more at PARP →
- NavlimetostatPhase 3
- AnvumetostatPhase 2
- AZD3470Phase 2
- TNG456Phase 2
- TNG462Phase 2
- CeralasertibPhase 3
- AzenosertibPhase 3
- NDI-219216Phase 2
- DostarlimabApprovedMismatch repair deficient (MSI-high) pancreatic ductal adenocarcinomaEndometrial cancerColorectal cancer
- PembrolizumabApprovedMismatch repair deficient (MSI-high) pancreatic ductal adenocarcinomaTriple-negative breast cancer (TNBC)Non-small-cell lung cancer
- CadonilimabApprovedCervical cancerGastric & gastro-oesophageal junction cancer
- CamrelizumabApprovedOesophageal cancerHepatocellular carcinomaNon-small-cell lung cancer
- Camrelizumab + rivoceranibApprovedHepatocellular carcinoma
- CemiplimabApprovedNon-small-cell lung cancerMelanomaPD-L1-high non-small-cell lung cancer without a driver mutation
- IvonescimabApprovedNon-small-cell lung cancerColorectal cancerTriple-negative breast cancer (TNBC)
- NivolumabApprovedMelanomaNon-small-cell lung cancerRenal cell carcinoma
- +23 more at PD-1 →
- SelinexorApprovedEndometrial cancerMultiple myelomaDiffuse large B-cell lymphoma
- OSE2101Phase 3
- KRT-232Phase 2
- EprenetapoptNegative
How tumours escape
Records tied to this stage that describe resistance, evasion or tolerance. The resistance atlas lists the routes class by class.
- preclinical evidenceindustryDestroy the truncated androgen receptor that hormone drugs cannot touch
In advanced prostate cancer the AR-V7 splice variant of the androgen receptor lacks the ligand-binding domain that enzalutamide and abiraterone act on, and its presence predicts resistance. A degrader or N-terminal binder that removes the whole protein, variants included, would still work; AR-V7 is already measurable in circulating tumour cells.
- preclinical evidenceresearchTurn off the error-prone repair that manufactures resistance mutations
Under treatment stress, cancer cells switch on sloppy DNA copying that generates the mutations they need to survive. Blocking that machinery could stop resistance being invented.
- 2024rctNICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patientsNew England Journal of Medicinechanged practice
- 2024translationalNICHE-2: a single dose of ipilimumab and two of nivolumab before surgery clears dMMR colon cancer in most patientsNew England Journal of Medicinechanged practice
- 2023translationalAUGMENT-101: revumenib, the first menin inhibitor, in relapsed leukaemias driven by KMT2A rearrangement or NPM1 mutationNaturechanged practice
- 2023rctCodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancerNew England Journal of Medicinechanged practice
- 2021rctOlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancerNew England Journal of Medicinechanged practice
- 2018rctSOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancerNew England Journal of Medicinechanged practice
Measured by
Biomarkers, tests and assays in the corpus that read this stage in a patient.
- FoundationOne CDxNGS tissue
- BRACAnalysis CDxGermline NGS
- myChoice CDxNGS tissue
- FoundationFocus CDxBRCANGS tissue
- FoundationOne Liquid CDxNGS plasma
- PD-L1 IHC 22C3 pharmDxIHC
- PD-L1 IHC 28-8 pharmDxIHC
- VENTANA MMR RxDx PanelIHC
- MSI by PCR (Promega MSI Analysis System and equivalents)PCR
- Tumour mutational burden (FoundationOne CDx and equivalents)NGS tissue
Open questions
What is not known at this stage: the atlas's own questions, the bottlenecks it bears on, and the ideas in the corpus that try to answer them.
- Which HRD test predicts PARP-inhibitor benefit best, and does HRD persist after platinum?
- Will PRMT5 and WRN inhibitors reproduce the PARP story?
- being tested at scaleresearchA bone drug to prevent breast cancer in BRCA1 carriers
BRCA1 breast cancers seem to grow from cells driven by the RANK signal. Denosumab blocks it and is already used for bone. A trial is testing whether it prevents these cancers.
- being tested at scaleresearchA funded programme of organ-preservation trials to avoid radical surgery
For some cancers, drugs and radiotherapy can now cure without removing the organ, sparing patients a stoma, a lost voice or a removed bladder. A dedicated programme would run the trials to prove where this is safe.
- being tested at scaleclinicAutomatic germline testing for every cancer type where it changes care
Anyone with ovarian, pancreatic, metastatic prostate or mismatch-repair-deficient colorectal cancer should be tested for inherited mutations, yet testing rates fall well short. Making it an automatic, opt-out laboratory step triggered by pathology, as reflex mismatch-repair testing already is, would close the gap.
- being tested at scaleclinicGet every Lynch syndrome carrier onto the right dose of aspirin
Aspirin roughly halves bowel cancer in Lynch syndrome, and a dose trial is defining how little is needed. Most carriers are still not prescribed it; the task is to fix prescribing.
- being tested at scaleMolecular-class-directed adjuvant therapy in endometrial cancer
Give adjuvant treatment by the tumour's molecular class rather than by stage and grade: nothing for POLE-mutated, immunotherapy for MMRd, chemotherapy plus targeted agents for p53-abnormal, hormones for NSMP.
- being tested at scalepolicyOffer everyone at 30 a test for the cancer genes that matter
Most people with BRCA or Lynch mutations do not know until they get cancer. Testing everyone once for a short list of high-impact genes would find them in time to prevent it.
- being tested at scalepolicyPopulation germline screening for hereditary cancer genes with cascade testing
Most people carrying a high-risk cancer gene do not know it until someone in the family gets cancer. Offer testing to all adults so carriers can be protected before that happens.
- being tested at scaleclinicStanding reflex biomarker panels per tumour type, run without an oncologist's order
For each cancer type, agree the set of stains and tests that are always needed, and have the lab run them automatically on diagnosis rather than waiting for someone to ask.
- early clinicalresearchA frameshift neoantigen vaccine for Lynch syndrome carriers as the first preventive cancer vaccine approval
People with Lynch syndrome have a very high lifetime cancer risk from a predictable set of mutations. Vaccinate them against those shared mutations before cancer appears.
- early clinicalindustryA randomised trial of a shared-antigen vaccine to prevent Lynch syndrome cancers
Lynch syndrome tumours share predictable mutations the immune system can target. A vaccine in early trials could be tested to see if it prevents polyps and cancers in carriers.
50 more ideas are linked to this stage's pathways, targets and terms; see the rankings →
Key evidence
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
- 2024rctIMerge: imetelstat, a telomerase inhibitor, for transfusion-dependent lower-risk MDS after erythropoietin has failedThe Lancetchanged practice
- 2024rctNICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patientsNew England Journal of Medicinechanged practice
- 2024translationalNICHE-2: a single dose of ipilimumab and two of nivolumab before surgery clears dMMR colon cancer in most patientsNew England Journal of Medicinechanged practice
- 2023translationalAUGMENT-101: revumenib, the first menin inhibitor, in relapsed leukaemias driven by KMT2A rearrangement or NPM1 mutationNaturechanged practice
- 2023rctCodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drugThe Lancetchanged practice
- 2023rctCodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancerNew England Journal of Medicinechanged practice
- 2023rctDeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancerNew England Journal of Medicinechanged practice
- 2023basicMRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted CancerCancer Discovery
- 2023rctNAPOLI-3: NALIRIFOX versus gemcitabine plus nab-paclitaxel as first treatment for metastatic pancreatic cancerThe Lancetchanged practice
- 2023rctRUBY: dostarlimab with chemotherapy for advanced or recurrent endometrial cancerNew England Journal of Medicinechanged practice
- 2022translationalCercek 2022: six months of dostarlimab alone made rectal cancer disappear in every patient with mismatch-repair deficiencyNew England Journal of Medicinechanged practice
- 2022rctDostarlimab alone cures mismatch-repair-deficient rectal cancer without surgery or radiotherapyNew England Journal of Medicinechanged practice
src/data/mechanics-atlas.ts). Players, medicines, escape routes, tests, ideas and papers are resolved from the knowledge graph at build time through the stage's pathways, targets and terms, so every item here has its own page and sources. Where a section is missing, the corpus has no record tied to the stage yet. Nothing here is medical advice; see about and methodology. Stage 4.2 of 56.