Kirsten rat sarcoma virus oncogene homolog G13A mutant (KRAS G13A)

KRAS G13A is a specific oncogenic mutation in the Kirsten rat sarcoma virus oncogene homolog (KRAS) protein, characterized by the substitution of glycine with alanine at codon 13. This mutation occurs within the P-loop of the GTP-binding domain, a region critical for the protein's catalytic function. The G13A substitution impairs both intrinsic and GTPase-activating protein (GAP)-mediated GTP hydrolysis, effectively locking the protein in a constitutively active, GTP-bound state. This persistent activation drives continuous signaling through downstream effector pathways, most notably the MAPK/ERK and PI3K/AKT cascades, which promote uncontrolled cell growth, survival, and metabolic reprogramming. KRAS G13A is frequently identified in colorectal, lung, and pancreatic cancers, where it acts as a potent driver of malignancy and is associated with poor clinical outcomes. Furthermore, the presence of this mutation typically confers resistance to standard-of-care anti-EGFR monoclonal antibodies, such as cetuximab and panitumumab. While direct, allele-specific inhibitors for G13A are currently in early development, therapeutic efforts are increasingly focused on pan-RAS inhibitors like RMC-6236 and combination strategies that target multiple nodes within the RAS signaling network.

Other names

KRAS p.G13AKRAS Gly13AlaKRAS codon 13 mutationKRAS G13A mutant protein

Direct inhibition of the mutant KRAS protein by binding to allosteric pockets (e.g., switch II) to prevent GTP binding or effector interaction, or indirect inhibition by blocking downstream signaling nodes such as MEK, ERK, and PI3K.