Kirsten rat sarcoma virus oncogene homolog G12D mutant (KRAS G12D)

KRAS G12D is a specific oncogenic mutant of the Kirsten rat sarcoma virus oncogene homolog (KRAS) protein, characterized by a glycine-to-aspartic acid substitution at codon 12 (OncoKB, NIH). This mutation impairs the protein's intrinsic GTPase activity and its ability to interact with GTPase-activating proteins (GAPs), effectively locking the protein in a constitutively active, GTP-bound ON state (NIH, JETIR). As a central molecular switch, the active KRAS G12D protein continuously triggers downstream signaling cascades, primarily the MAPK/ERK and PI3K/AKT pathways, which drive uncontrolled cell proliferation, survival, and metabolic reprogramming (NIH, MD Anderson). It is the most frequent KRAS mutation in pancreatic ductal adenocarcinoma (PDAC) and is also highly prevalent in colorectal and non-small cell lung cancers (NIH, ASCO). Historically considered undruggable due to the lack of a reactive cysteine residue and a lack of deep binding pockets, recent therapeutic breakthroughs have introduced selective non-covalent inhibitors, covalent ON-state inhibitors, and proteolysis-targeting chimeras (PROTACs) that specifically target the G12D mutant (Drug Hunter, MSKCC, Astellas Pharma).

Other names

KRAS p.G12DKRAS glycine 12 to aspartic acidKRAS Asp12KRAS G12D

KRAS G12D-targeted agents utilize several mechanisms: non-covalent inhibition of the Switch II pocket to block effector binding, covalent ON-state inhibition via tri-complex formation with cyclophilin A, and targeted protein degradation (PROTACs) to induce proteasomal destruction of the mutant protein (NIH, Revolution Medicines, Astellas Pharma).