GTPase KRAS (G13D mutation) (KRAS G13D)

KRAS G13D is a specific oncogenic variant of the KRAS protein, characterized by a glycine-to-aspartic acid substitution at residue 13. This missense mutation impairs the protein's intrinsic GTPase activity and its sensitivity to GTPase-activating proteins (GAPs), leading to a state where the protein is persistently bound to GTP and remains constitutively active [1, 5]. As a critical node in cellular signaling, the mutant protein drives overactivation of the MAPK/ERK and PI3K/AKT pathways, which are essential for cell growth, differentiation, and survival [7, 11]. KRAS G13D is a major driver in various cancers, particularly colorectal cancer (occurring in ~8-20% of cases), as well as lung and pancreatic cancers [2, 7]. Unlike other common KRAS mutations such as G12C or G12V, clinical and biochemical data suggest that G13D-mutant colorectal cancers may retain some sensitivity to anti-EGFR monoclonal antibodies like cetuximab, potentially due to its unique interaction with the tumor suppressor neurofibromin (NF1) [3, 11, 12]. Current therapeutic strategies include the development of pan-KRAS inhibitors, RAS-multi inhibitors (e.g., RMC-6236), and mRNA-based vaccines to specifically target the aberrant signaling of this variant [6, 8].

Other names

Kirsten rat sarcoma viral oncogene homolog G13DK-Ras G13Dp.G13D mutationKRAS codon 13 mutationGTPase KRAS G13D

Drugs targeting this variant utilize several mechanisms: direct inhibition of active RAS (RAS-multi inhibitors binding to the ON-state), gene silencing through RNA interference (RNAi) to prevent protein expression, or immunological targeting via mRNA vaccines that present mutant peptide antigens to T cells [1, 6, 8]. Additionally, anti-EGFR antibodies act upstream to reduce total RAS signaling in specific contexts like G13D colorectal cancer [3, 5].