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The most important cancer gene was declared undruggable for 40 years. Then a pocket was found, and now a pan-RAS drug is in phase 3 for pancreatic cancer.
The KRAS roadmap begins with the gene's discovery as a human oncogene and decades of failure, when farnesyltransferase inhibitors did not work, until the Shokat lab found the switch-II pocket and sotorasib and adagrasib were approved in NSCLC. The current step goes beyond G12C with non-covalent G12D inhibitors and pan-RAS(ON) tri-complex inhibitors such as daraxonrasib in pancreatic cancer, and the emerging step anticipates a first pancreatic approval, combinations, KRAS vaccines, mutant-KRAS TCR-T and RAS degraders. The speculative end is neoadjuvant RAS inhibition and interception in high-risk cyst carriers. KRAS drives the three common cancers with the lowest survival; the route links pancreatic, colorectal and NSCLC, the KRAS target, KRAS and RAS inhibitors and the undruggable-drivers bottleneck.
KRAS identified as a human oncogene (1982). Farnesyltransferase inhibitors fail (1990s-2000s); RAS lacks druggable pockets and binds GTP with picomolar affinity. NCI launches the RAS Initiative (2013).
Shokat lab finds a covalent pocket in KRAS G12C (2013). Sotorasib (2021) and adagrasib (2022) approved in NSCLC; colorectal cancer needs EGFR antibody combination.
Non-covalent G12D inhibitors (MRTX1133, zoldonrasib); pan-RAS(ON) tri-complex inhibitors (daraxonrasib) with ~14.5-month OS in second-line pancreatic cancer; phase 3 RASolute 302 enrolled; first-line and adjuvant trials start. Divarasib, olomorasib, and elironrasib improve on first-generation G12C drugs.
Expected first pancreatic cancer approval for a RAS inhibitor; combinations with chemotherapy, EGFR/SHP2 inhibitors, and immunotherapy; KRAS vaccines (ELI-002) in adjuvant pancreatic cancer; mutant-KRAS TCR-T; RAS degraders.
Neoadjuvant RAS inhibition making pancreatic cancer resectable; MCED-detected early pancreatic cancer treated with RAS inhibitor + vaccine; interception in high-risk pancreatic cyst carriers.
Every era's records, trial outcomes and papers, and every watch item, as JSON.
Probability ranges are named estimates that the claim is borne out on roughly a five-year horizon. They are meant to be argued with: propose a revision with your name and reasoning via a pull request to src/data/confidence.ts.
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The mechanism that let one drug address G12D, G12V and G12R together, which is why the RASolute 302 trial could enrol unselected pancreatic cancer and nearly double survival.
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 has little effect in bowel cancer. Responses are still modest and short-lived compared with EGFR or ALK inhibitors in lung cancer.
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.
The reason pancreatic cancer is the proving ground for RAS drugs: nearly every tumour depends on the same mutant protein, so a drug that works against it works for nearly every patient.
Shares Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable, Adagrasib, KRAS G12C-mutant pancreatic ductal adenocarcinoma, Sotorasib.
Shares Revolution Medicines, RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression, KRAS G12C-mutant pancreatic ductal adenocarcinoma, Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall.
Shares Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy, Revolution Medicines, RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression, Daraxonrasib.
Shares Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable, RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression, KRAS G12C-mutant pancreatic ductal adenocarcinoma, Sotorasib.
Shares RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression, Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall, KRAS & RAS inhibitors, The undruggable drivers.
Shares Revolution Medicines, RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression, Daraxonrasib, Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall.
Shares KRAS G12C inhibitor + anti-EGFR antibody (colorectal), 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, Sotorasib.
Shares CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug, Daraxonrasib, KRAS G12C-mutant pancreatic ductal adenocarcinoma, Sotorasib.