Kirsten rat sarcoma viral oncogene homolog mutant (G12C, G12D, G12V) (KRAS (G12C, G12D, G12V))

KRAS (Kirsten rat sarcoma viral oncogene homolog) is a proto-oncogene encoding a membrane-bound, small GTPase that acts as a molecular switch to transmit signals from cell surface receptors to intracellular effectors, regulating cell proliferation, differentiation, and survival. Mutations at codon 12 (G12C, G12D, G12V) are among the most frequent oncogenic events in solid tumors, particularly pancreatic, lung, and colorectal cancers. These mutations impair GTPase activity, resulting in constitutive activation of the KRAS protein and persistent stimulation of downstream signaling pathways, including RAF-MEK-ERK and PI3K-AKT. Targeted therapies have recently been developed for these mutants: KRAS G12C can be covalently targeted by small molecule inhibitors (e.g., sotorasib, adagrasib), while G12D and G12V mutants are being addressed through non-covalent small molecules and peptide inhibitors. These advances represent a shift for previously “undruggable” oncogenic KRAS proteins, although resistance and tumor heterogeneity remain major therapeutic challenges[2][3][5][6].

Other names

KRAS mutantRas family GTPase mutantsKRAS G12CKRAS G12DKRAS G12VKRAS p.G12Cp.G12Dp.G12V

Covalent inhibition (irreversible binding to mutant cysteine for G12C) [2][6] Non-covalent inhibition (for G12D; locks KRAS mutant in inactive state) [6] Peptide inhibition of nucleotide exchange and effector interaction [5]