# The undruggable drivers

Source: https://onco.cc/bottlenecks/b-undruggable-targets/  
OnCo record `b-undruggable-targets` (Bottleneck). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.

## Summary

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.

## Fields

- Kind: Bottleneck
- Last checked: 2026-09-08
- Stage: biology
- Severity: critical
- Metrics: Cancers carrying a RAS mutation (US incidence-weighted estimate): ~19% of all cancers (Prior, Hood & Hartley, Cancer Research 2020); TP53 mutation frequency across 12 major tumour types (TCGA pan-cancer): 42% of tumours (Kandoth et al., Nature 2013)
- Causes: 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.

## Sources

- Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017): https://doi.org/10.1038/nrc.2017.36
- NCI RAS Initiative: https://www.cancer.gov/research/key-initiatives/ras
- Prior et al., The frequency of Ras mutations in cancer (Cancer Research 2020): https://doi.org/10.1158/0008-5472.CAN-19-3682

## Connected records

- roadmaps: [Drug discovery roadmap: screening in mice → maps of dependency → designing in silico](https://onco.cc/roadmaps/drug-discovery-roadmap/), [Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome](https://onco.cc/roadmaps/epigenetics-roadmap/), [KRAS roadmap: undruggable → G12C → pan-RAS](https://onco.cc/roadmaps/kras-roadmap/), [Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question](https://onco.cc/roadmaps/pancreatic-roadmap/), [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)
- ideas: [A drug screen that only rewards killing sleeping cancer cells](https://onco.cc/ideas/idea-bio2-dormancy-selective-screen/), [A guaranteed purchase prize for the first drug against a named hard target](https://onco.cc/ideas/idea-bio1-undruggable-market-commitment/), [A precompetitive consortium for the twenty hardest cancer targets](https://onco.cc/ideas/idea-bio1-undruggable-open-consortium/), [A synthetic lethality map for every cancer driver in every tissue context](https://onco.cc/ideas/idea-moon-synthetic-lethality-map-every-driver/), [A target de-risking index that counts failures as well as successes](https://onco.cc/ideas/idea-tr2-target-failure-index/), [AI-designed proteins that grip the floppy parts of cancer drivers](https://onco.cc/ideas/idea-bio1-ai-binders-disordered-regions/), [An open degrader consortium against every undruggable driver transcription factor](https://onco.cc/ideas/idea-moon-open-degrader-consortium/), [An open map of which cancer proteins any drug can stick to](https://onco.cc/ideas/idea-bio1-covalent-ligandability-atlas/), [An open-science consortium on the undruggable drivers, open until a candidate](https://onco.cc/ideas/idea-fund-precompetitive-undruggable-consortium/), [Antibodies that see mutant KRAS and p53 fragments displayed on the cell surface](https://onco.cc/ideas/idea-bio1-pmhc-bispecifics-public-drivers/), [Attack the backup copy when a tumour has lost the original gene](https://onco.cc/ideas/idea-bio1-paralog-synthetic-lethality/), [Break up the liquid droplets where oncogenic transcription happens](https://onco.cc/ideas/idea-bio1-condensate-disruptors/), [Covalent chemistry for the RAS mutations that still have no drug](https://onco.cc/ideas/idea-bio1-pan-ras-covalent-g12d/), [Degrade the damaged p53 protein rather than trying to repair it](https://onco.cc/ideas/idea-bio1-mutant-p53-degrader/), [Degraders for the fusion proteins that drive childhood sarcomas](https://onco.cc/ideas/idea-bio1-fusion-tf-degraders/), [Design protein degraders small enough to get into the brain](https://onco.cc/ideas/idea-bio2-brain-penetrant-glue-degraders/), [Destroy the truncated androgen receptor that hormone drugs cannot touch](https://onco.cc/ideas/idea-bio1-arv7-degrader/), [Drag cancer's surface and secreted proteins to the cell's recycling bin](https://onco.cc/ideas/idea-bio1-lytac-surface-degraders/), [Engineered bacteria that live in tumours and manufacture drugs there](https://onco.cc/ideas/idea-bio2-engineered-bacteria-payloads/), [Extend p53 reactivation beyond the Y220C mutation](https://onco.cc/ideas/idea-bio1-p53-mutant-reactivator-expansion/), [Find E3 ligases that only tumours have, and build degraders around them](https://onco.cc/ideas/idea-bio1-tumour-restricted-e3-atlas/), [Instruct tumour cells to make antibodies against their own oncoprotein](https://onco.cc/ideas/idea-bio1-mrna-intrabodies/), [Macrocyclic peptides to cover protein surfaces that pills cannot](https://onco.cc/ideas/idea-bio1-macrocycle-ppi-campaign/), [Milestone prizes for first-in-class mechanisms reaching human proof of concept](https://onco.cc/ideas/idea-fund-first-in-class-prize/), [Molecular glues that break the MYC-MAX partnership](https://onco.cc/ideas/idea-bio1-myc-max-molecular-glue/), [mRNA-delivered MYC decoy proteins instead of MYC inhibitors](https://onco.cc/ideas/idea-bio1-omomyc-mrna/), [Off-the-shelf KRAS vaccines after pancreatic cancer surgery](https://onco.cc/ideas/idea-shared-kras-vaccine-adjuvant/), [RAS(ON) inhibitors to convert unresectable pancreatic cancer to resectable](https://onco.cc/ideas/idea-ras-inhibitor-neoadjuvant-pdac/), [Run small-cell lung cancer as one platform with shared controls and subtype stratification](https://onco.cc/ideas/idea-lung-small-cell-platform-with-shared-controls-and-subtypes/), [Scale up public drug development that takes academic assets to phase 1](https://onco.cc/ideas/idea-fund-national-drug-development-office/), [Screen glue-like compounds against every cancer cell line and publish it](https://onco.cc/ideas/idea-bio1-glue-degrader-atlas/), [Small molecules that cut the RNA message of an undruggable oncogene](https://onco.cc/ideas/idea-bio1-rna-targeting-small-molecules/), [Starve MYC-driven tumours by blocking protein production machinery](https://onco.cc/ideas/idea-bio1-translation-dependency-myc/), [Switch off an undruggable oncogene permanently with epigenetic editing](https://onco.cc/ideas/idea-bio1-epigenetic-silencing-in-vivo/), [Turn a brake back on: drugs that reactivate the PP2A phosphatase](https://onco.cc/ideas/idea-bio1-pp2a-activators/), [Turn chromosomal chaos into a weakness with KIF18A inhibitors](https://onco.cc/ideas/idea-bio1-cin-vulnerability-kif18a/), [Use antibodies to deliver protein-destroying drugs into the right cells](https://onco.cc/ideas/idea-bio1-antibody-degrader-conjugates/), [Use the brain's own transport door to carry antibody drugs across](https://onco.cc/ideas/idea-bio2-transferrin-shuttle-adc/), [Watch for the cancer changing cell type before the biopsy says neuroendocrine, and act on it](https://onco.cc/ideas/idea-prostate-plasticity-surveillance-before-it-is-neuroendocrine/), [WRN inhibitors: a second synthetic-lethal win for mismatch-repair cancers](https://onco.cc/ideas/idea-bio1-wrn-msi-programme/)
- collections: [DepMap (Cancer Dependency Map)](https://onco.cc/collections/depmap/), [Open Targets Platform](https://onco.cc/collections/open-targets/)
- cancers: [Acute myeloid leukaemia](https://onco.cc/cancers/aml/), [Chordoma](https://onco.cc/cancers/chordoma/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [NUT carcinoma (midline carcinoma with NUTM1 rearrangement)](https://onco.cc/cancers/nut-carcinoma/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Sarcomas (soft tissue, bone, GIST)](https://onco.cc/cancers/sarcoma/)
- technologies: [AI-driven drug & target discovery](https://onco.cc/technologies/ai-drug-design/), [KRAS & RAS inhibitors](https://onco.cc/technologies/kras-inhibitors/), [Off-the-shelf cancer vaccines](https://onco.cc/technologies/shared-antigen-vaccine/), [Oligonucleotide therapeutics](https://onco.cc/technologies/antisense-sirna/), [PROTACs & molecular glues (targeted protein degradation)](https://onco.cc/technologies/protac-degrader/), [Synthetic lethality approaches](https://onco.cc/technologies/synthetic-lethality-approaches/)
- targets: [BRAF](https://onco.cc/targets/braf/), [KMT2A (MLL) rearrangement](https://onco.cc/targets/kmt2a/), [KRAS](https://onco.cc/targets/kras/), [Menin](https://onco.cc/targets/menin/), [NPM1 mutation](https://onco.cc/targets/npm1/), [TP53](https://onco.cc/targets/tp53/)
- drugs: [Adagrasib](https://onco.cc/drugs/adagrasib/), [Daraxonrasib](https://onco.cc/drugs/daraxonrasib/), [ELI-002 7P](https://onco.cc/drugs/eli-002-7p/), [Elironrasib](https://onco.cc/drugs/elironrasib/), [Eprenetapopt](https://onco.cc/drugs/eprenetapopt/), [MRTX1133](https://onco.cc/drugs/mrtx1133/), [Revumenib](https://onco.cc/drugs/revumenib/), [Sotorasib](https://onco.cc/drugs/sotorasib/), [Ziftomenib](https://onco.cc/drugs/ziftomenib/), [Zoldonrasib](https://onco.cc/drugs/zoldonrasib/)
- companies: [Arvinas](https://onco.cc/companies/arvinas/), [C4 Therapeutics](https://onco.cc/companies/c4-therapeutics/), [Elicio Therapeutics](https://onco.cc/companies/elicio-therapeutics/), [Frontier Medicines](https://onco.cc/companies/frontier-medicines/), [Kymera Therapeutics](https://onco.cc/companies/kymera/), [Monte Rosa Therapeutics](https://onco.cc/companies/monte-rosa/), [Nurix Therapeutics](https://onco.cc/companies/nurix/), [Quanta Therapeutics](https://onco.cc/companies/quanta-therapeutics/), [Revolution Medicines](https://onco.cc/companies/revolution-medicines/)
- institutions: [Broad Institute of MIT and Harvard](https://onco.cc/institutions/broad-institute/), [Centro Nacional de Investigaciones Oncológicas (CNIO)](https://onco.cc/institutions/cnio/), [Frederick National Laboratory for Cancer Research](https://onco.cc/institutions/frederick-national-lab/), [Laura and Isaac Perlmutter Cancer Center at NYU Langone Health](https://onco.cc/institutions/nyu-perlmutter/), [Lustgarten Foundation](https://onco.cc/institutions/lustgarten-foundation/), [National Cancer Institute (NIH)](https://onco.cc/institutions/nci/), [Sanford Burnham Prebys Medical Discovery Institute](https://onco.cc/institutions/sanford-burnham-prebys/), [Wellcome Sanger Institute](https://onco.cc/institutions/wellcome-sanger/)
- pathways: [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [Synthetic lethality: paired dependencies](https://onco.cc/pathways/synthetic-lethality-map/)
- trials: [AMPLIFY-7P](https://onco.cc/trials/amplify-7p/), [CodeBreaK 200](https://onco.cc/trials/codebreak-200/), [KRYSTAL-12](https://onco.cc/trials/krystal-12/), [RASolute 302](https://onco.cc/trials/rasolute-302/)
- key papers: [Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib](https://onco.cc/key-papers/paper-lynch-egfr-activating-mutations-gefitinib-nejm-2004/), [AlphaFold 2: predicting protein structures to near-experimental accuracy](https://onco.cc/key-papers/paper-alphafold2-jumper-nature-2021/), [AUGMENT-101: revumenib, the first menin inhibitor, in relapsed leukaemias driven by KMT2A rearrangement or NPM1 mutation](https://onco.cc/key-papers/paper-augment-101-revumenib-menin-nature-2023/), [Cancer genome landscapes: about 140 driver genes, and each tumour needs only a handful](https://onco.cc/key-papers/paper-vogelstein-cancer-genome-landscapes-science-2013/), [CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug](https://onco.cc/key-papers/paper-codebreak-200-lancet-2023/), [CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer](https://onco.cc/key-papers/paper-codebreak-300-nejm-2023/), [Comprehensive genomic profiles of small cell lung cancer](https://onco.cc/key-papers/paper-george-sclc-genomic-profiles-nature-2015/), [Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy](https://onco.cc/key-papers/paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024/), [Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without](https://onco.cc/key-papers/paper-depmap-tsherniak-cell-2017/), [DeLLphi-301: tarlatamab, a DLL3-targeting T-cell engager, in previously treated small-cell lung cancer](https://onco.cc/key-papers/paper-dellphi-301-nejm-2023/), [Drugging the 'undruggable' cancer targets](https://onco.cc/key-papers/paper-dang-nat-rev-cancer/), [First imatinib trial: a pill that switched off the enzyme driving chronic myeloid leukaemia](https://onco.cc/key-papers/paper-druker-imatinib-phase1-nejm-2001/), [Huggins and Hodges 1941: the effect of castration, of oestrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate](https://onco.cc/key-papers/paper-huggins-hodges-castration-serum-phosphatases-prostate-1941/), [Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer](https://onco.cc/key-papers/paper-soda-eml4-alk-fusion-nature-2007/), [IMerge: imetelstat, a telomerase inhibitor, for transfusion-dependent lower-risk MDS after erythropoietin has failed](https://onco.cc/key-papers/paper-imerge-imetelstat-mds-lancet-2024/), [Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes](https://onco.cc/key-papers/paper-almoguera-kras-codon-12-pancreatic-cell-1988/), [NAPOLI-3: NALIRIFOX versus gemcitabine plus nab-paclitaxel as first treatment for metastatic pancreatic cancer](https://onco.cc/key-papers/paper-napoli-3-lancet-2023/), [Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable](https://onco.cc/key-papers/paper-ostrem-kras-g12c-nature-2013/), [Punctuated evolution of prostate cancer genomes](https://onco.cc/key-papers/paper-baca-punctuated-evolution-chromoplexy-cell-2013/), [Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer](https://onco.cc/key-papers/paper-tomlins-tmprss2-ets-fusion-science-2005/), [SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer](https://onco.cc/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/), [Stupp 2005: temozolomide added to radiotherapy for newly diagnosed glioblastoma](https://onco.cc/key-papers/paper-stupp-temozolomide-nejm-2005/), [The first PROTAC: a chimeric molecule that tags a protein for destruction](https://onco.cc/key-papers/paper-protac-concept-sakamoto-pnas-2001/), [The Frequency of Ras Mutations in Cancer](https://onco.cc/key-papers/paper-prior-cancer-res/), [The mutational landscape of lethal castration-resistant prostate cancer](https://onco.cc/key-papers/paper-grasso-mutational-landscape-lethal-crpc-nature-2012/)
- terms: [Chromoplexy](https://onco.cc/terms/chromoplexy/)
- people: [Eli Broad](https://onco.cc/people/eli-broad/)

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