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

KRAS G12C is a specific mutant form of the KRAS protein, a small GTPase that acts as a molecular switch in cell signaling pathways [1.1.1]. The G12C mutation involves a glycine-to-cysteine substitution at codon 12, which impairs the protein's intrinsic GTPase activity and locks it in a constitutively active, GTP-bound state [1.3.2]. This leads to persistent activation of downstream pathways like MAPK and PI3K, driving uncontrolled cell proliferation and survival in various cancers [1.3.2]. It is most prevalent in non-small cell lung cancer (NSCLC), where it occurs in approximately 13% of cases, and is also found in colorectal and pancreatic cancers [1.2.3, 1.4.4]. Historically considered "undruggable" due to its high affinity for GTP and lack of traditional binding pockets, KRAS G12C became a therapeutic target with the discovery of an allosteric "switch II" pocket [1.3.4]. Modern drugs like sotorasib and adagrasib are covalent inhibitors that specifically bind to the mutant cysteine residue when the protein is in its inactive GDP-bound state [1.1.1]. This binding effectively traps the protein in its inactive conformation, shutting down oncogenic signaling and inhibiting tumor growth [1.3.2]. Clinical efficacy is often limited by the emergence of resistance, which can occur through secondary mutations or the activation of bypass signaling pathways [1.3.4]. Ongoing research focuses on combination therapies and next-generation inhibitors to overcome these resistance mechanisms and improve patient outcomes [1.1.2, 1.4.3].

Other names

KRAS p.G12CGTPase KRas G12CKRAS G12C mutant proteinKirsten rat sarcoma 2 viral oncogene homolog G12C

Covalent inhibition of the GDP-bound (inactive) state of the KRAS G12C mutant protein by binding to the switch II pocket.