GTPase KRas (G13C mutant) (KRAS G13C)

GTPase KRas (G13C mutant) is an oncogenic variant of the KRAS protein, a small GTPase that functions as a critical molecular switch in intracellular signaling pathways (UniProt, 2024). Under physiological conditions, KRAS cycles between an active GTP-bound state and an inactive GDP-bound state to regulate essential processes such as cell growth, differentiation, and survival. The G13C mutation involves a glycine-to-cysteine substitution at codon 13, which impairs the protein's ability to hydrolyze GTP, thereby locking it in a constitutively active state (NIH, 2024). This persistent activation drives aberrant signaling through downstream effectors, most notably the MAPK/ERK and PI3K/AKT pathways, leading to uncontrolled cell proliferation and tumorigenesis in various cancers, including non-small cell lung cancer and colorectal cancer (Patsnap, 2024). While KRAS was historically considered undruggable, the unique cysteine residue in the G13C mutant provides a specific site for the development of covalent inhibitors. Modern therapeutic strategies include mutant-selective covalent inhibitors and tri-complex inhibitors that form a stable complex with the mutant protein and intracellular chaperones like cyclophilin A to sterically block effector binding (Revolution Medicines, 2024).

Other names

KRAS G13CK-Ras G13Cp21 Ras G13CKirsten rat sarcoma viral oncogene homolog G13CKRAS p.G13C

Covalent inhibition of the cysteine residue at position 13, tri-complex formation with cyclophilin A to sterically block effector binding, and locking the protein in the inactive GDP-bound state to disrupt oncogenic signaling (Revolution Medicines, 2024; eLife, 2023).