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

KRAS-G12C is a mutant form of the Kirsten rat sarcoma viral oncogene homolog, a member of the RAS family of small GTPases, with glycine at position 12 replaced by cysteine (G12C). KRAS is a critical molecular switch regulating cell proliferation, differentiation, and survival through cycling between GDP-bound inactive and GTP-bound active states[7][3]. The G12C mutation renders KRAS constitutively active or impairs GTP hydrolysis, which drives oncogenic signaling in several cancers, most notably lung adenocarcinoma and colorectal cancer[4][3]. Covalent inhibitors specifically exploit a novel pocket revealed by the G12C mutation, achieving mutant-selective inactivation without affecting wild-type KRAS[4][8]. KRAS-G12C has become a major therapeutic target, with several FDA-approved and investigational drugs showing activity in patients with KRAS-G12C-mutant tumors[8][5]. Challenges remain, including primary and acquired resistance, tumor heterogeneity, and pathway redundancy[1][3][8].

Other names

KRAS(G12C)K-Ras p.G12CKRAS c.34G>TKRAS glycine 12 to cysteineG12C KRAS mutant

Covalent inhibition of the mutant cysteine at position 12, specifically targeting the G12C residue and locking KRAS in an inactive (GDP-bound) state[1][4][8] - Disruption of effector (e.g., RAF) binding and downstream signaling (such as the MAPK pathway)[4][3]