Kirsten rat sarcoma virus proto-oncogene GTPase (KRAS) G12D mutant (KRAS G12D)

KRAS G12D is a specific mutant form of the Kirsten rat sarcoma virus proto-oncogene GTPase (KRAS), characterized by the substitution of glycine with aspartic acid at codon 12 (NIH, 2025; ResearchGate, 2025). This mutation is a dominant oncogenic driver, particularly prevalent in pancreatic ductal adenocarcinoma (PDAC), where it occurs in approximately 40% of cases, as well as in colorectal and non-small cell lung cancers (UCLA Health, 2026; NIH, 2025). The G12D substitution impairs the protein's intrinsic GTPase activity and its sensitivity to GTPase-activating proteins (GAPs), effectively locking KRAS in a constitutively active, GTP-bound state (JETIR, 2025; ACS, 2025). This persistent activation triggers downstream signaling through the MAPK and PI3K pathways, promoting uncontrolled cell proliferation, survival, and metabolic reprogramming (NIH, 2024; NIH, 2025). While historically considered undruggable due to the lack of a reactive cysteine for covalent targeting, recent therapeutic advances have introduced selective non-covalent inhibitors like MRTX1133, covalent tri-complex inhibitors such as RMC-9805, and targeted protein degraders like setidegrasib (ASP3082) (NIH, 2025; MSKCC, 2026). These agents aim to inhibit the oncogenic signaling of KRAS G12D-mutant tumor cells by either blocking effector interactions or inducing the degradation of the mutant protein (NIH, 2025; UCLA Health, 2026).

Other names

KRAS G12Dp.G12D KRASKirsten rat sarcoma viral oncogene homolog G12DKRAS Asp12KRAS G12D mutant protein

Non-covalent inhibition of the switch II pocket, covalent inhibition via tri-complex formation with cyclophilin A, and targeted protein degradation via PROTAC technology.