About this condition
KRAS Mutation
KRAS (Kirsten rat sarcoma viral oncogene homolog, chromosome 12p12.1) is the most frequently mutated oncogene in human cancer — found in approximately 25% of all cancers, including ~30-40% of NSCLC (adenocarcinoma), ~40-50% of colorectal cancer, and ~90% of pancreatic cancer. KRAS mutations constitutively activate the RAS-RAF-MEK-ERK signaling pathway, driving cell proliferation. For four decades, KRAS was considered 'undruggable' due to the protein's smooth surface lacking a druggable binding pocket.
Sotorasib (Lumakras, FDA 2021) was the first drug to successfully target KRAS — specifically the G12C mutation (glycine to cysteine at position 12). Sotorasib exploits the unique cysteine at position 12 to covalently and irreversibly bind KRAS G12C in its inactive GDP-bound state, locking the protein off. KRAS G12C is found in approximately 13% of NSCLC (adenocarcinoma), 3% of CRC, and 1-2% of other cancers. Adagrasib (Krazati) is a second FDA-approved KRAS G12C inhibitor with longer half-life and CNS penetration.
The KRAS revolution is expanding beyond G12C. KRAS G12D inhibitors (MRTX1133 and others) are in clinical trials — critically important because G12D is the most common KRAS mutation across all cancers (representing ~36% of KRAS-mutant pancreatic cancer). G12V and other codon inhibitors are in preclinical development. Additionally, KRAS mutation status determines anti-EGFR antibody eligibility in CRC — KRAS-mutant CRC does NOT respond to cetuximab or panitumumab, making KRAS testing mandatory before anti-EGFR therapy.
KRAS-mutant CRC does NOT respond to anti-EGFR antibodies (cetuximab, panitumumab) — testing is MANDATORY before prescribing. Giving anti-EGFR therapy to a KRAS-mutant patient wastes time and money while delaying effective treatment.
- Gene locus
- KRAS (12p12.1)
