KRAS proto-oncogene, GTPase, G12C mutant (KRAS^G12C^)

KRAS^G12C^ is a mutant form of the KRAS protein with a cysteine substitution at position 12, which impairs normal GTPase activity and causes persistent signaling for cell growth and survival[3][5][6]. This constitutive activation is a driver of oncogenesis in several cancer types, most notably non-small cell lung cancer. The discovery of a unique pocket adjacent to the mutant cysteine residue has enabled the development of covalent inhibitors such as sotorasib and adagrasib, which specifically target KRAS^G12C^ by irreversibly binding to the mutant protein and blocking its ability to propagate downstream oncogenic signals[3][4][5][6]. KRAS^G12C^ is now routinely tested as a predictive biomarker for targeted therapy selection and is a major example of a previously "undruggable" oncogene becoming amenable to precision medicine. Resistance mechanisms, including secondary KRAS mutations and activation of alternative pathways, remain important therapeutic challenges[5].

Other names

KRAS G12CKRAS p.G12CKras glycine 12 to cysteine mutantKRAS c.34G>TKRAS p.Gly12Cys

Covalent inhibition: drugs form a covalent bond with the cysteine 12 residue in the switch-II pocket, locking KRAS^G12C^ in the inactive GDP-bound form and blocking downstream signaling