KRAS roadmap: undruggable → G12C → pan-RAS
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.
KRAS drives the three deadliest common cancers. Progress came from chemistry (covalent switch-II binders), then from a new mechanism (tri-complex RAS(ON) inhibitors), and next from degraders, vaccines, and combinations.
- 1982-2012historic
Discovery and failure
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).
- 2013-2021historic
The switch-II pocket
Shokat lab finds a covalent pocket in KRAS G12C (2013). Sotorasib (2021) and adagrasib (2022) approved in NSCLC; colorectal cancer needs EGFR antibody combination.
- 2023-2026current
Beyond G12C
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.
- 2026-2029emerging
Approval and combinations
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.
- 2030+speculative35%–60%likely
Speculative
Neoadjuvant RAS inhibition making pancreatic cancer resectable; MCED-detected early pancreatic cancer treated with RAS inhibitor + vaccine; interception in high-risk pancreatic cyst carriers.
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.
Story
topDiscovery and failure
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).
The switch-II pocket
Shokat lab finds a covalent pocket in KRAS G12C (2013). Sotorasib (2021) and adagrasib (2022) approved in NSCLC; colorectal cancer needs EGFR antibody combination.
Sotorasib (Lumakras) was the first drug to hit KRAS, approved in 2021 after four decades of failure.
Adagrasib was the second KRAS G12C inhibitor, with a long half-life and brain penetration, and is approved in lung and colorectal cancer.
In colorectal cancer, a KRAS blocker alone barely works because the cell turns EGFR up; adding an EGFR antibody stops that.
Beyond G12C
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.
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.
Revolution Medicines is the leading RAS company, with daraxonrasib in phase 3 for pancreatic cancer.
Approval and combinations
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.
Speculative
Neoadjuvant RAS inhibition making pancreatic cancer resectable; MCED-detected early pancreatic cancer treated with RAS inhibitor + vaccine; interception in high-risk pancreatic cyst carriers.
A single blood test intended to screen for dozens of cancers at once, including ones with no screening today.
Pancreatic cancer is the deadliest common cancer. Almost every tumour carries a KRAS mutation, and for the first time drugs against it are in pivotal trials.