Kirsten rat sarcoma viral oncogene homolog GTPase G12C mutant (KRAS G12C)

Kirsten rat sarcoma viral oncogene homolog (KRAS) is a small GTPase enzyme crucial for regulating cell signaling related to growth and proliferation. The protein acts as a molecular switch, cycling between inactive (GDP-bound) and active (GTP-bound) states; activation leads to downstream signaling via the MAPK pathway and others, promoting proliferation and survival. The G12C mutation, a glycine to cysteine substitution at codon 12, is one of the most common KRAS mutations driving oncogenesis, particularly in lung adenocarcinoma, pancreatic ductal carcinoma, and colorectal carcinoma. This mutation locks KRAS in a constitutively active state, leading to uncontrolled cell signaling. KRAS G12C has become a major therapeutic target, with several covalent small-molecule inhibitors approved by the FDA (sotorasib, adagrasib) or in clinical development (divarasib, opnurasib, BI-0474, ARS-1620) that irreversibly modify the cysteine at position 12 in the inactive state, effectively blocking abnormal signaling driving cancer growth. Drugs targeting KRAS G12C represent a landmark in precision oncology due to the historical "undruggable" nature of RAS proteins. KRAS G12C is considered a highly validated therapeutic target, with well-characterized roles in cancer biology and clinical efficacy established for several inhibitors.

Other names

KRasK-RasKRASKRAS4AKRAS4BKirsten rat sarcomaRAS (context-dependent)KRAS G12C mutant

All FDA-approved and clinical-stage drugs listed above are covalent inhibitors that specifically target the cysteine at position 12 (the G12C mutation) in the GDP-bound inactive state of KRAS. They bind to a unique allosteric pocket ("switch-II pocket"), preventing KRAS activation and downstream signaling through pathways driving cell proliferation and survival.