{"id":"kras-roadmap","name":"KRAS roadmap: undruggable → G12C → pan-RAS","route":"/roadmaps/kras-roadmap/","eras":[{"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).","status":"historic","refs":[{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/","tldr":"KRAS is the most commonly mutated cancer gene, called 'undruggable' for 40 years until 2021."}],"trials":[],"papers":[]},{"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.","status":"historic","refs":[{"id":"sotorasib","kind":"drug","name":"Sotorasib","route":"/drugs/sotorasib/","status":"approved","tldr":"Sotorasib (Lumakras) was the first drug to hit KRAS, approved in 2021 after four decades of failure."},{"id":"adagrasib","kind":"drug","name":"Adagrasib","route":"/drugs/adagrasib/","status":"approved","tldr":"Adagrasib was the second KRAS G12C inhibitor, with a long half-life and brain penetration, and is approved in lung and colorectal cancer."},{"id":"kras-plus-egfr-crc","kind":"pairing","name":"KRAS G12C inhibitor + anti-EGFR antibody (colorectal)","route":"/pairings/kras-plus-egfr-crc/","tldr":"In colorectal cancer, a KRAS blocker alone has little effect because the cell turns EGFR up; adding an EGFR antibody stops that."}],"trials":[],"papers":[]},{"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.","status":"current","refs":[{"id":"daraxonrasib","kind":"drug","name":"Daraxonrasib","route":"/drugs/daraxonrasib/","status":"approved","tldr":"The first drug that blocks all active RAS variants, approved by the FDA in August 2026 for metastatic pancreatic cancer, where KRAS drives 90% of tumours."},{"id":"revolution-medicines","kind":"company","name":"Revolution Medicines","route":"/companies/revolution-medicines/","tldr":"Revolution Medicines is the leading RAS company, with daraxonrasib in phase 3 for pancreatic cancer."}],"trials":[],"papers":[]},{"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.","status":"emerging","refs":[{"id":"shared-antigen-vaccine","kind":"technology","name":"Off-the-shelf cancer vaccines","route":"/technologies/shared-antigen-vaccine/","status":"phase-3","tldr":"Off-the-shelf cancer vaccines target antigens shared across patients, such as mutant KRAS or HER2 peptides, so they are made in advance rather than per person. Sipuleucel-T is still the only approved therapeutic cancer vaccine in the US; tolerance to self-antigens and weak past results hold them back."},{"id":"tcr-t","kind":"technology","name":"TCR-T cell therapy","route":"/technologies/tcr-t/","status":"approved","tldr":"T cells engineered with a receptor that sees fragments of proteins inside the cancer cell, reaching targets CAR-T cannot."}],"trials":[],"papers":[]},{"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.","status":"speculative","refs":[{"id":"mced","kind":"technology","name":"Multi-cancer early detection (MCED)","route":"/technologies/mced/","status":"phase-3","tldr":"A single blood test intended to screen for dozens of cancers at once, including ones with no screening today."},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/","tldr":"Almost every pancreatic tumour carries a KRAS mutation, and for the first time drugs against it work: daraxonrasib nearly doubled survival in previously treated disease in 2026. Pancreatic cancer has been the hardest common cancer to treat once advanced; that is what is starting to change."}],"trials":[],"papers":[]}],"watch":[]}