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

The Mutant human KRAS G12C protein is a specific oncogenic variant of the Kirsten rat sarcoma viral oncogene homolog (KRAS), a small GTPase that functions as a molecular switch in cell signaling. Under normal conditions, KRAS cycles between an active GTP-bound state and an inactive GDP-bound state to regulate pathways such as RAF-MEK-ERK and PI3K-AKT-mTOR, which control cell proliferation and survival (Source 1.1.2, 1.3.4). The G12C mutation, a glycine-to-cysteine substitution at codon 12, impairs the protein's ability to hydrolyze GTP, effectively locking it in a constitutively active state that drives tumorigenesis (Source 1.3.2, 1.3.3). This mutation is a major driver in several malignancies, particularly non-small cell lung cancer (NSCLC), where it occurs in approximately 13% of cases, as well as colorectal and pancreatic cancers (Source 1.2.1, 1.2.4). Although KRAS was long considered "undruggable," the identification of a targetable Switch II allosteric pocket near the mutant cysteine has led to the development of selective covalent inhibitors (Source 1.1.3, 1.1.4). Drugs like sotorasib and adagrasib work by binding irreversibly to the cysteine residue, trapping the protein in its inactive GDP-bound conformation and halting oncogenic signaling (Source 1.1.4, 1.3.2). Clinical use of these inhibitors has transformed the treatment landscape for KRAS G12C-mutant cancers, though therapeutic challenges such as acquired resistance and hepatotoxicity persist (Source 1.1.5, 1.2.5).

Other names

KRAS p.G12CGTPase KRas G12C mutantc-K-ras G12CK-ras 2 G12C

Covalent inhibition of the GDP-bound (inactive) state by binding to the Switch II pocket