The undruggable drivers
The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.
KRAS G12C showed that 'undruggable' is a technology problem, not a law: a covalent pocket that exists only in one mutant state yielded sotorasib and adagrasib within a decade of its discovery. But most of the oncogenic burden of human cancer sits on proteins with no enzymatic pocket, flat protein-protein interfaces, or intrinsically disordered regions: MYC, most RAS alleles, mutant and wild-type TP53, transcription factors such as the fusion oncoproteins of sarcomas and leukaemias, and phosphatases. The therapies we have act on downstream nodes with narrow therapeutic windows and rapid feedback reactivation. New modalities, including pan-RAS(ON) inhibitors, molecular glues and degraders, antisense, and peptide or vaccine strategies presenting mutant epitopes, are the first serious assault on this class. RAS mutations alone occur in roughly a fifth of all cancers, so each success reshapes several diseases at once.
- Transcription factors and RAS proteins lack deep hydrophobic pockets, so conventional small molecules cannot bind them tightly.
- Picomolar affinity of RAS for GTP defeats competitive nucleotide-site inhibitors.
- Downstream inhibition (MEK, ERK, PI3K) triggers feedback reactivation and toxicity in normal tissue before it suppresses the tumour.
- Loss-of-function tumour suppressors such as TP53 cannot be inhibited; they must be restored, degraded in their mutant form, or exploited through synthetic lethality.
- Fusion oncoproteins and MYC are intrinsically disordered, which frustrates structure-based design.
- The NCI RAS Initiative at the Frederick National Laboratory works as an open consortium on RAS structure, biochemistry and screening.
- Revolution Medicines' daraxonrasib (RMC-6236), a pan-RAS(ON) tri-complex inhibitor, is in phase 3 in pancreatic cancer (RASolute 302) after showing activity across KRAS alleles.
- MRTX1133 and other non-covalent KRAS G12D inhibitors extend the covalent-pocket lesson to the most common pancreatic allele.
- Arvinas, Kymera, Nurix, C4 Therapeutics and Monte Rosa are building PROTAC degraders and molecular glues that remove proteins without needing a functional pocket.
- Menin inhibitors (revumenib, ziftomenib) show that a transcriptional complex can be drugged at a protein-protein interface in KMT2A-rearranged and NPM1-mutant leukaemia.
- Off-the-shelf mutant-KRAS vaccines (ELI-002) and TCR therapies present undruggable proteins to the immune system instead of blocking them.
Nearly all cancer drugs are found by killing fast-growing cells. Sleeping cells survive them. A screen designed around dormant cells would find a different class of drug.
Governments promised in advance to buy vaccines that did not yet exist, and they got made. The same promise could be made for a drug against a target everyone has given up on.
No single company will spend a decade on a target that might be impossible. A shared, openly published effort across the twenty hardest targets spreads that risk.
For each cancer-causing mutation, find every gene the cancer cell newly depends on, in every tissue, so that even undruggable drivers get druggable partners.
For each drug target, show how many programmes have been tried against it and how many failed, so new teams know what they are up against.
Many cancer proteins have shapeless, flexible regions that drugs cannot hold on to. New protein design software may be able to invent binders that clamp them.
Cancer's most important drivers, such as MYC and mutant p53, cannot be blocked with normal drugs. Pool effort and share results openly to build molecules that destroy them instead.
Most cancer proteins have never been tested to see whether a small molecule can attach to them at all. A public map of what is chemically reachable would tell the field where to aim.
Companies and public funders would pool money and scientists to crack the hardest cancer proteins, such as MYC and mutant p53, sharing everything openly until there is a real drug candidate, then competing on the final product.
Cells chop up their internal proteins and display the pieces on their surface. That means even undruggable proteins inside the cell can be attacked from outside by the immune system.
Tumours often lose one of a pair of near-identical genes. They then depend entirely on the remaining copy, which a drug can block, killing only the cancer.
Some cancer-driving proteins gather into droplet-like blobs inside the nucleus to switch genes on. Drugs that dissolve those blobs might switch the cancer programme off.
One RAS mutation can now be drugged because it offers a reactive handle. Most RAS mutations do not, so new chemistry is needed to grab other amino acids.
Some faulty p53 proteins do not just stop protecting the cell; they actively help the cancer. Removing them entirely may be easier than fixing them.
Some sarcomas in children are caused by two genes fused into one abnormal protein. That protein is the whole disease, but no drug binds it. Destroying it instead of blocking it could work.
New drugs that destroy cancer proteins are usually too big to enter the brain. Making much smaller versions could bring this approach to brain tumours.
In advanced prostate cancer, a shortened form of the hormone receptor loses the very part existing drugs bind to. A drug that destroys the whole protein would still work.
Some cancer proteins sit on the cell surface or float outside cells, where protein-destroying drugs cannot reach. A different trick can drag them inside to be broken down.
Some harmless bacteria naturally grow in the low-oxygen core of tumours. Engineering them to produce immune-activating drugs turns them into tiny factories inside the tumour.
One faulty version of the p53 guardian protein can now be repaired by a drug that plugs a hole in it. Systematically hunting for similar holes in other faulty versions could help far more patients.
Protein-destroying drugs work by hijacking cellular waste-disposal machines. Using a machine that is mostly present in cancer cells would make these drugs safer.
Deliver genetic instructions so the cancer cell itself manufactures a molecule that traps its driver protein inside the cell.
Many cancer proteins work by touching each other over broad flat surfaces. Small pills cannot cover those, but ring-shaped peptides can, and some can still be taken orally.
Pay a fixed prize, of tens of millions, to the first team to show that a completely new way of attacking cancer works in patients, so that the riskiest early bets are rewarded even before a product exists.
MYC drives many cancers but has no drug because it has no pocket. A glue-like molecule that jams its required partner protein could switch it off.
A decoy protein can bind MYC's partner and block it. Delivering the instructions for that decoy as mRNA in a fat nanoparticle avoids having to inject the protein itself.
The US government already runs a small programme that turns academic cancer discoveries into drugs ready for human trials. Scale it up tenfold and copy it in other countries.
Some drugs work by sticking two proteins together so one destroys the other. These are usually found by luck. A large systematic search, published openly, would find many more.
If the protein cannot be drugged, target the message that makes it. Small molecules can now recognise folded shapes in RNA and recruit an enzyme that chops it up.
Cancers driven by MYC need to make proteins at an unusually fast rate. Slowing the cell's protein factory hits them harder than it hits normal cells.
Instead of blocking a cancer protein, add a chemical off-switch to its gene so the cell stops making it. Early versions of this tool are being tested in other diseases.
Cells have an enzyme, PP2A, that removes the growth signals cancer relies on. Cancers switch it off. Drugs that switch it back on are an unusual and largely untried approach.
Highly unstable tumours survive constant chromosome mistakes by leaning on a motor protein. Blocking it kills unstable cancer cells while sparing normal ones.
Drugs that destroy proteins can hit healthy cells too. Attaching them to an antibody that only docks onto tumour cells would keep them where they are needed.
The brain has natural transport doors for iron. Attaching a key that fits those doors can smuggle large drug molecules in, a trick now working in Alzheimer's medicines.
Cancers with faulty DNA proof-reading depend on one particular unwinding enzyme to survive. Blocking it kills them and spares normal cells.
IMerge validated telomerase as a drug target in cancer, decades after its discovery, and gave a second-line option for MDS patients whose anaemia no longer responds to erythropoietin or luspatercept. The hint of clonal reduction is what makes the drug interesting beyond transfusion counts. Cytopenias require close monitoring in the first cycles.
Revumenib proved that a transcriptional dependency, rather than a kinase, can be drugged in leukaemia, opening treatment for two genetic subgroups that together cover roughly a third of AML plus most infant ALL. It is now approved and is being combined with venetoclax-azacitidine and intensive chemotherapy in front-line trials. Single-agent remissions are often short without transplant.
Patients with KRAS G12C lung cancer that has progressed after chemo-immunotherapy can take an oral KRAS inhibitor instead of docetaxel and gain a somewhat longer time to progression with fewer severe side effects, but should understand that most tumours become resistant within a year and that survival is not improved. KRAS G12C testing is worthwhile, but first-generation inhibitors are a step rather than a cure; combinations and next-generation inhibitors are the active research fronts.
Patients with metastatic colorectal cancer carrying a KRAS G12C mutation (about 3-4% of cases) who have exhausted standard chemotherapy now have a targeted option that works far better than trifluridine-tipiracil or regorafenib. The higher sotorasib dose is clearly superior, and the EGFR antibody is essential because KRAS inhibition alone barely works in bowel cancer. Responses are still modest and short-lived compared with EGFR or ALK inhibitors in lung cancer.
Patients with small-cell lung cancer that has relapsed after chemotherapy now have a drug that works far better than topotecan or lurbinectedin, and it is the first T-cell engager approved for a solid tumour. Treatment requires inpatient monitoring for the first doses because of cytokine release syndrome, which most centres now manage on a short-stay basis. It does not yet apply to first-line treatment, where trials are ongoing.
For fit patients with newly diagnosed metastatic pancreatic cancer, a FOLFIRINOX-type regimen is now proven to be better than gemcitabine plus nab-paclitaxel, settling a long-standing debate. The absolute gain is about two months of median survival, and the regimen is more toxic for the gut. Whether liposomal irinotecan adds anything over conventional irinotecan (standard FOLFIRINOX) has never been tested head-to-head.
The shape of nearly every protein is now available to any researcher in seconds instead of years, which shortens the path from a cancer target to a designed molecule. It does not by itself produce drugs: binding pockets, dynamics and cellular context still need experiment.
DepMap is the lookup table drug hunters use to ask: which cancers would die if we blocked this gene, and how would we recognise them? It generated targets such as WRN and PRMT5-MTAP now in clinical trials, and it is public.
There are not thousands of cancer genes, and any one patient's tumour is driven by only a few of them. That makes targeted sequencing panels sensible, but because most drivers are lost tumour suppressors, drugs exist for only a minority, which is why the same group turned to early detection.
The most frequently mutated oncogene in cancer stopped being undruggable, and patients with KRAS G12C lung and bowel cancers now have targeted pills. The approach, exploiting a mutation-created chemical handle and an inactive-state pocket, has become a template for other hard targets.
Patients with newly diagnosed glioblastoma who are fit and under about 70 receive six weeks of radiotherapy with daily temozolomide followed by six monthly cycles of temozolomide; this is still the backbone of treatment two decades later. Testing MGMT methylation identifies who benefits most and guides decisions in older patients. Median survival with the regimen remains only around 15-20 months, and no drug since has clearly improved on it, which is why glioblastoma is a priority for new approaches.
Druker's 2001 imatinib paper turned the idea of hitting a cancer's specific molecular engine into a working medicine. For people with CML it began the shift from a fatal disease treated with interferon or transplant to one managed with a daily tablet. It also set expectations, later tempered, that every cancer might have its own imatinib.
Instead of blocking a cancer protein, a drug can now remove it entirely, which works even for proteins without a druggable active site and can overcome resistance driven by target overexpression or mutation. Several degraders are in late-stage trials for breast and prostate cancer.
Pages like this
not linked directly; found by shared links- TechnologyCRISPR functional genomics
Shares Switch off an undruggable oncogene permanently with epigenetic editing, A drug screen that only rewards killing sleeping cancer cells, Attack the backup copy when a tumour has lost the original gene, Degraders for the fusion proteins that drive childhood sarcomas.
- TechnologyMolecular glue discovery platforms
Shares C4 Therapeutics, The first PROTAC: a chimeric molecule that tags a protein for destruction, Nurix Therapeutics, Monte Rosa Therapeutics.
- TermSynthetic lethality
Shares Attack the backup copy when a tumour has lost the original gene, Turn chromosomal chaos into a weakness with KIF18A inhibitors, WRN inhibitors: a second synthetic-lethal win for mismatch-repair cancers, A synthetic lethality map for every cancer driver in every tissue context.
- PairingMenin inhibitor + venetoclax + azacitidine
Shares NPM1 mutation, AUGMENT-101: revumenib, the first menin inhibitor, in relapsed leukaemias driven by KMT2A rearrangement or NPM1 mutation, KMT2A (MLL) rearrangement, Ziftomenib.
- CompanyAmgen
Shares Turn chromosomal chaos into a weakness with KIF18A inhibitors, CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer, CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug, DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer.
- BottleneckThe valley of death between lab and product
Shares First imatinib trial: a pill that switched off the enzyme driving chronic myeloid leukaemia, AlphaFold 2: predicting protein structures to near-experimental accuracy, Scale up public drug development that takes academic assets to phase 1, Open Targets Platform.
- PersonKevan M. Shokat
Shares Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable, Adagrasib, Sotorasib, KRAS & RAS inhibitors.
- BottleneckAcquired resistance to every therapy
Shares Destroy the truncated androgen receptor that hormone drugs cannot touch, WRN inhibitors: a second synthetic-lethal win for mismatch-repair cancers, The first PROTAC: a chimeric molecule that tags a protein for destruction, A synthetic lethality map for every cancer driver in every tissue context.