Kirsten rat sarcoma virus oncogene homolog G13C mutant (KRAS G13C)

KRAS G13C is an oncogenic mutant of the Kirsten rat sarcoma virus oncogene homolog (KRAS), a small GTPase that functions as a molecular switch in cellular signal transduction. The mutation involves a single amino acid substitution of glycine with cysteine at position 13, which significantly impairs the protein's ability to hydrolyze GTP to GDP. This biochemical defect locks the KRAS protein in a constitutively active, GTP-bound state, leading to the persistent activation of downstream signaling cascades such as the MAPK/ERK and PI3K/AKT/mTOR pathways. These pathways are critical for regulating cell growth, proliferation, and survival, and their dysregulation drives the development and progression of various malignancies, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). Historically considered undruggable, the G13C mutant has recently become a focus of targeted therapy due to the reactive cysteine residue, which can be targeted by covalent small-molecule inhibitors. Emerging therapeutic strategies include allele-specific covalent inhibitors and pan-KRAS inhibitors designed to trap the protein in its inactive state or sterically block effector interactions.

Other names

KRAS p.G13CKirsten rat sarcoma virus oncogene homolog G13CKRAS codon 13 cysteine mutationp21 Ras G13C

Covalent inhibition of the mutant cysteine residue at position 13, tri-complex formation with cyclophilin A (CypA) to sterically block effector binding, and inactive-state (OFF-state) trapping to prevent nucleotide exchange and downstream signaling.