Kirsten rat sarcoma virus proto-oncogene GTPase G13C mutant (KRAS G13C)

KRAS G13C is a specific missense mutation in the KRAS gene where the glycine at position 13 is replaced by a cysteine. This mutation occurs frequently in colorectal and lung cancers, leading to a protein that is constitutively active by impairing its ability to hydrolyze GTP into GDP. As a member of the small GTPase family, KRAS G13C acts as a molecular switch that, when mutated, remains in the 'on' position, driving uncontrolled cell growth and survival through the MAPK/ERK and PI3K/AKT signaling pathways. While historically considered undruggable, the presence of the reactive cysteine residue at position 13 provides a unique pocket for the development of covalent inhibitors, similar to the approach used for KRAS G12C. Current therapeutic strategies include direct covalent inhibitors, pan-RAS inhibitors, and indirect approaches such as SOS1 inhibitors that prevent the transition of KRAS to its active state.

Other names

KRAS proto-oncogene, GTPase G13Cp21 Ras G13CK-Ras 2 G13CGTPase KRas G13C mutant

Direct covalent inhibition of the cysteine residue at position 13 or indirect inhibition via SOS1 blockade to prevent GTP loading, thereby locking the protein in an inactive GDP-bound state and disrupting downstream MAPK and PI3K signaling pathways.