KRAS protein G12C mutant (KRAS G12C)

The KRAS protein G12C mutant is a variant of the KRAS small GTPase, a member of the RAS family, produced by a missense mutation that substitutes glycine for cysteine at amino acid position 12[1][3]. This mutation leads to impaired GTPase activity, hyperactivating downstream MAPK/ERK signalling and promoting oncogenesis[2][3]. The G12C mutation creates a unique nucleophilic cysteine, which allows for the rational design of covalent inhibitors that selectively trap KRAS G12C in its inactive GDP-bound state, preventing cell proliferation in KRAS G12C-driven cancers. The mutant protein is predominantly found in non-small cell lung cancer and, to a lesser extent, in colorectal and pancreatic tumors[1][2][3]. KRAS G12C has recently become druggable with FDA-approved covalent inhibitors, representing a major milestone in overcoming the formerly "undruggable" nature of RAS oncoproteins[2][3]. The protein is post-translationally modified and is predominantly membrane-associated, where it interacts with multiple effectors and regulators[1][4]. Its activity and function in the cancer cell are shaped by its interactions, localization, and modifications. KRAS G12C is also significant for mediating immune evasion through effects on PD-L1 expression and the tumor microenvironment[2]. Drug resistance, tumor heterogeneity, and immune modulation remain therapeutic challenges for KRAS G12C-targeted therapies[2][3].

Other names

KRAS p.G12CKRAS G12CKRAS glycine 12 to cysteine mutantKRAS c.34G>TMutant KRAS G12C

Covalent inhibition of KRAS G12C at the switch-II pocket, locking the protein in its inactive GDP-bound state and blocking downstream MAPK pathway signalling