G12Cmutant

G12Cmutant refers to a specific alteration in the KRAS gene, where the amino acid glycine is replaced by cysteine at codon 12 (KRAS p.G12C). This is a somatic missense mutation and is not typically inherited. The change affects the KRAS protein, a small GTPase that controls cell growth signaling. In many cancers, G12C disrupts normal GTP hydrolysis, promoting continued activation of KRAS and downstream pathways that drive cell proliferation.

Biologically, KRAS G12C contributes to constitutive signaling through pathways such as MAPK/ERK and PI3K-AKT. The mutation alters the cycling between inactive (GDP-bound) and active (GTP-bound) states, leading to persistent growth signals that can support tumor development and progression. G12C is one of the more well-characterized KRAS alterations and has become a focal point for targeted therapy development.

In terms of prevalence, KRAS G12C is especially common in non-small cell lung cancer, where it is a major KRAS subtype, particularly among smokers. It is also detected in pancreatic and colorectal cancers, but at lower frequencies. Detection is typically performed through tumor tissue sequencing or circulating tumor DNA assays, using targeted panels or broader genomic profiling.

Therapeutically, G12C specific inhibitors have transformed the treatment landscape. Covalent inhibitors such as sotorasib and adagrasib selectively bind the mutant cysteine in KRAS G12C and lock the protein in an inactive state, reducing downstream signaling. Sotorasib received approval for KRAS G12C-mutant NSCLC after prior therapy, with adagrasib following in subsequent years. Ongoing research addresses resistance mechanisms and combination strategies to extend benefit for patients with G12Cmutant cancers.