Kirsten rat sarcoma virus oncogene homolog G12C (KRAS G12C) (KRAS G12C)

Kirsten rat sarcoma virus oncogene homolog (KRAS) is a small GTPase that functions as a critical molecular switch in cellular signaling pathways, including the RAS/MAPK and PI3K/AKT/mTOR cascades [5, 6]. Under normal physiological conditions, KRAS cycles between an active GTP-bound state and an inactive GDP-bound state to regulate cell growth, differentiation, and survival [3, 10]. The G12C mutation involves a single amino acid substitution of glycine with cysteine at codon 12, which impairs the protein's intrinsic GTPase activity and its response to GTPase-activating proteins (GAPs) [1, 10]. This results in the protein being predominantly locked in the active, GTP-bound state, leading to constitutive downstream signaling and oncogenic transformation [5, 10]. KRAS G12C is a major driver in several malignancies, most notably appearing in approximately 13% of non-small cell lung cancers and 3% of colorectal cancers [12, 17]. Therapeutic targeting of this specific mutant has been achieved through the development of covalent inhibitors, such as sotorasib and adagrasib, which exploit the nucleophilic nature of the mutant cysteine residue [2, 6]. These drugs bind to a specific pocket (Switch II) that is only present in the inactive GDP-bound conformation, effectively trapping the mutant protein in its "off" state and inhibiting tumor growth [2, 10]. Despite clinical success, challenges such as acquired resistance through secondary mutations (e.g., H95, Y96) and bypass signaling remain significant hurdles in treatment [2, 18].

Other names

KRAS G12CK-Ras G12CKirsten rat sarcoma viral oncogene homolog G12Cp21 G12CG12C mutant KRAS

Covalent inhibition of the inactive GDP-bound state of the KRAS G12C mutant protein, locking it in an inactive conformation and preventing downstream signaling.