KRAS protein GTPase, glycine-to-cysteine substitution at position 12 (KRAS G12C)

KRAS protein GTPase with a glycine-to-cysteine substitution at position 12 (KRAS G12C) is a mutant form of the KRAS gene encoding a critical signal transduction enzyme. This mutation locks KRAS in a constitutively active state, promoting uncontrolled cell proliferation and survival, and is prevalent in several solid tumors—especially lung adenocarcinomas. Historically considered "undruggable," KRAS G12C has become a major oncology target following the FDA approval of direct covalent inhibitors such as sotorasib and adagrasib. These drugs specifically target the mutant cysteine in an allosteric pocket, trapping the protein in its inactive GDP-bound state and blocking its oncogenic signaling. Despite breakthroughs, resistance and tumor heterogeneity remain significant hurdles, and biomarker-driven patient selection is essential for therapy.

Other names

KRAS G12CKRAS (G12C)Kirsten rat sarcoma viral oncogene homologue G12Cp.G12C KRASRAS G12C

Covalent inhibition: Drugs selectively bind the mutant cysteine in the switch-II pocket (SIIP) when KRAS G12C is in its inactive GDP-bound state, irreversibly inactivating the protein and blocking downstream proliferative signaling. Allosteric modulation of KRAS conformation, preventing GTP loading and effector interaction.