Kirsten rat sarcoma virus proto-oncogene GTPase (KRAS) G13D (KRAS G13D)

KRAS G13D is a specific oncogenic variant of the Kirsten rat sarcoma virus proto-oncogene GTPase, where glycine at position 13 is replaced by aspartic acid (UniProt). This mutation results in a protein that is constitutively active, persistently signaling through downstream pathways such as MAPK/ERK and PI3K/AKT to promote cell growth and survival (NIH, 2020). KRAS G13D is a significant driver in several malignancies, most notably colorectal cancer, where it is found in roughly 7-10% of patients (ACS, 2023). Historically, KRAS mutations were thought to confer universal resistance to anti-EGFR therapies; however, KRAS G13D is a notable exception, as some patients respond to cetuximab due to the mutant's unique biochemical interaction with the NF1 tumor suppressor (Science Signaling, 2019). Current drug discovery efforts are focused on developing allele-specific, reversible inhibitors that bind to the Switch II pocket of the GDP-bound form (ACS Med. Chem. Lett., 2024). Additionally, indirect targeting strategies using SOS1 or SHP2 inhibitors are being explored to disrupt the activation cycle of the mutant protein (Patsnap, 2024). Despite these advances, therapeutic challenges remain, including the rapid development of resistance through bypass signaling and the difficulty of achieving high potency with small molecules (ACS, 2023).

Other names

KRAS p.G13DKRAS Gly13Aspp.G13DKirsten rat sarcoma 2 viral oncogene homolog G13D

KRAS G13D acts as a constitutively active molecular switch that drives oncogenic signaling through the MAPK and PI3K pathways (NIH, 2019). Unlike other KRAS mutants, G13D-mutant cells may retain sensitivity to EGFR inhibitors like cetuximab because the G13D mutation impairs binding to the NF1 tumor suppressor, leaving NF1 available to regulate wild-type RAS isoforms (Science Signaling, 2019). Novel therapeutic approaches include reversible inhibitors that target the Switch II pocket of the GDP-bound state, often utilizing a salt bridge with the aspartic acid residue at position 13 (ACS Med. Chem. Lett., 2024). Additionally, SOS1 and SHP2 inhibitors are used to block the nucleotide exchange and activation of the mutant protein (Patsnap, 2024).