G12Cmutated

G12Cmutated refers to cancers in which the KRAS gene carries a missense mutation at codon 12, changing glycine to cysteine (p.G12C). This substitution creates constitutively active KRAS signaling that promotes cell proliferation and survival.

Biochemical effect: KRAS cycles between active GTP-bound and inactive GDP-bound forms. The G12C alteration impairs intrinsic GTPase activity and makes KRAS signaling less dependent on upstream receptor signals, leading to continuous downstream pathway activation (MAPK, PI3K-AKT).

Epidemiology: G12C is the most common KRAS mutation in lung adenocarcinoma, and also occurs in colorectal and pancreatic cancers, though with different frequencies. It is a major driver mutation in a subset of non-small cell lung cancers, often associated with smoking.

Therapeutic implications: Historically considered difficult to target. Recent covalent inhibitors selectively bind the mutant cysteine 12 and lock KRAS in an inactive state. Sotorasib and adagrasib are approved for KRAS G12C-mutant non-small cell lung cancer after prior therapy; studies show activity in other G12C tumors. The development of these agents has spurred ongoing research into broader indications and combination strategies.

Detection: KRAS G12C status is determined by sequencing of tumor tissue or circulating tumor DNA. Comprehensive genomic profiling is commonly used to identify G12C and guide targeted therapy decisions.

Resistance and research: Tumors can develop resistance through secondary KRAS mutations or activation of compensatory pathways. Ongoing research explores combination strategies with SHP2, SOS1, MEK inhibitors, or immunotherapies to enhance efficacy and overcome resistance.