{"entity":{"id":"kras-roadmap","kind":"roadmap","name":"KRAS roadmap: undruggable → G12C → pan-RAS","aka":[],"tldr":"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.","summary":"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.","asOf":"2026-09-04","links":[{"label":"Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable (Nature 2013)","url":"https://doi.org/10.1038/nature12796"},{"label":"CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer (New England Journal of Medicine 2023)","url":"https://doi.org/10.1056/NEJMoa2308795"}],"tags":[],"related":["targeted-therapy-roadmap","pancreatic-roadmap","colorectal-roadmap","lung-cancer-evidence-roadmap"],"cancers":["pancreatic","colorectal","nsclc"],"sections":["targeted-therapy"],"technologies":["kras-inhibitors"],"targets":["kras"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"steps":[{"era":"1982-2012","title":"Discovery and failure","description":"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).","refs":["kras"],"status":"historic"},{"era":"2013-2021","title":"The switch-II pocket","description":"Shokat lab finds a covalent pocket in KRAS G12C (2013). Sotorasib (2021) and adagrasib (2022) approved in NSCLC; colorectal cancer needs EGFR antibody combination.","refs":["sotorasib","adagrasib","kras-plus-egfr-crc"],"status":"historic"},{"era":"2023-2026","title":"Beyond G12C","description":"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.","refs":["daraxonrasib","revolution-medicines"],"status":"current"},{"era":"2026-2029","title":"Approval and combinations","description":"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.","refs":["shared-antigen-vaccine","tcr-t"],"status":"emerging"},{"era":"2030+","title":"Speculative","description":"Neoadjuvant RAS inhibition making pancreatic cancer resectable; MCED-detected early pancreatic cancer treated with RAS inhibitor + vaccine; interception in high-risk pancreatic cyst carriers.","refs":["mced","pancreatic"],"status":"speculative"}],"watch":[]},"route":"/roadmaps/kras-roadmap/","neighbours":{"roadmap":[{"id":"colorectal-roadmap","kind":"roadmap","name":"Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation","route":"/roadmaps/colorectal-roadmap/"},{"id":"lung-cancer-evidence-roadmap","kind":"roadmap","name":"Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch","route":"/roadmaps/lung-cancer-evidence-roadmap/"},{"id":"pancreatic-roadmap","kind":"roadmap","name":"Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question","route":"/roadmaps/pancreatic-roadmap/"},{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}],"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"kras-g12c-pdac","kind":"cancer","name":"KRAS G12C-mutant pancreatic ductal adenocarcinoma","route":"/cancers/kras-g12c-pdac/"},{"id":"metastatic-pdac","kind":"cancer","name":"Metastatic pancreatic ductal adenocarcinoma","route":"/cancers/metastatic-pdac/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"section":[{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"technology":[{"id":"kras-inhibitors","kind":"technology","name":"KRAS & RAS inhibitors","route":"/technologies/kras-inhibitors/"},{"id":"mced","kind":"technology","name":"Multi-cancer early detection (MCED)","route":"/technologies/mced/"},{"id":"shared-antigen-vaccine","kind":"technology","name":"Off-the-shelf cancer vaccines","route":"/technologies/shared-antigen-vaccine/"},{"id":"tcr-t","kind":"technology","name":"TCR-T cell therapy","route":"/technologies/tcr-t/"}],"target":[{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"}],"drug":[{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/"},{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/"},{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/"}],"pairing":[{"id":"kras-plus-egfr-crc","kind":"pairing","name":"KRAS G12C inhibitor + anti-EGFR antibody (colorectal)","route":"/pairings/kras-plus-egfr-crc/"}],"company":[{"id":"revolution-medicines","kind":"company","name":"Revolution Medicines","route":"/companies/revolution-medicines/"}],"paper":[{"id":"paper-codebreak-200-lancet-2023","kind":"paper","name":"CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug","route":"/key-papers/paper-codebreak-200-lancet-2023/"},{"id":"paper-codebreak-300-nejm-2023","kind":"paper","name":"CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer","route":"/key-papers/paper-codebreak-300-nejm-2023/"},{"id":"paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024","kind":"paper","name":"Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy","route":"/key-papers/paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024/"},{"id":"paper-almoguera-kras-codon-12-pancreatic-cell-1988","kind":"paper","name":"Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes","route":"/key-papers/paper-almoguera-kras-codon-12-pancreatic-cell-1988/"},{"id":"paper-ostrem-kras-g12c-nature-2013","kind":"paper","name":"Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable","route":"/key-papers/paper-ostrem-kras-g12c-nature-2013/"}],"idea":[{"id":"idea-fund-precompetitive-undruggable-consortium","kind":"idea","name":"An open-science consortium on the undruggable drivers, open until a candidate","route":"/ideas/idea-fund-precompetitive-undruggable-consortium/"},{"id":"idea-pdac-ras-inhibitor-combinations-and-sequencing","kind":"idea","name":"RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression","route":"/ideas/idea-pdac-ras-inhibitor-combinations-and-sequencing/"}],"bottleneck":[{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}]}}