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

The Kirsten rat sarcoma virus oncogene homolog (KRAS) G12C mutant is a specific oncogenic variant of the KRAS protein, a small GTPase that functions as a critical molecular switch in intracellular signaling pathways [1]. In its wild-type form, KRAS cycles between an active GTP-bound state and an inactive GDP-bound state to regulate cell growth and survival [1]. The G12C mutation, characterized by a glycine-to-cysteine substitution at position 12, impairs the protein's ability to hydrolyze GTP, leading to a constitutively active state that drives malignant transformation [2]. This mutation is a frequent driver in solid tumors, most notably in approximately 13% of non-small cell lung cancers and 3% of colorectal cancers [3]. Therapeutic targeting of KRAS G12C was revolutionized by the development of small-molecule inhibitors that covalently bind to the mutant cysteine residue within the switch II pocket [2, 4]. These drugs, such as sotorasib and adagrasib, effectively lock the protein in its inactive GDP-bound conformation, thereby suppressing downstream signaling through the MAPK and PI3K pathways [4, 5]. Despite clinical success, challenges remain, including the development of acquired resistance through secondary KRAS mutations or activation of alternative signaling loops [3].

Other names

KRAS proto-oncogene, GTPasep21 RasK-Ras 2KRAS2RASK2KRAS G12C mutant peptide

Covalent binding to the cysteine residue at position 12 in the switch II pocket, locking the KRAS protein in its inactive GDP-bound state and preventing downstream signaling [2, 4].