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

The Kirsten rat sarcoma virus oncogene homolog G12C (KRAS G12C) mutant is a specific oncogenic variant of the KRAS protein, a small GTPase that functions as a molecular switch in cellular signaling. Under normal conditions, KRAS cycles between an active GTP-bound state and an inactive GDP-bound state to regulate pathways such as MAPK/ERK and PI3K/AKT, which control cell growth and survival (nih.gov, 1.2.3). The G12C mutation, characterized by a glycine-to-cysteine substitution at codon 12, impairs intrinsic GTP hydrolysis and locks the protein in a predominantly active state, driving malignant transformation (patsnap.com, 1.4.3). This mutation is highly prevalent in non-small cell lung cancer (NSCLC) and is also found in colorectal and pancreatic cancers (nih.gov, 1.1.1). For decades, KRAS was considered "undruggable" due to its high affinity for GTP and lack of accessible binding pockets (merck.com, 1.5.3). However, the discovery of a targetable switch II pocket (SIIP) enabled the development of covalent inhibitors like sotorasib and adagrasib (nih.gov, 1.2.1). These drugs specifically bind to the mutant cysteine residue, trapping KRAS G12C in its inactive GDP-bound conformation and effectively suppressing tumor growth (lumakras.com, 1.5.2).

Other names

KRAS p.G12CGTPase KRas G12CKRASG12CKirsten rat sarcoma viral oncogene homolog G12C

Covalent inhibition of the inactive GDP-bound state by binding to the Switch II pocket (SIIP), trapping the protein in an inactive conformation and preventing nucleotide exchange.