Kirsten rat sarcoma virus oncogene homolog G12D (KRAS G12D)

Kirsten rat sarcoma virus oncogene homolog G12D (KRAS G12D) is a mutant isoform of the KRAS protein, a member of the small GTPase family that functions as a critical molecular switch in intracellular signaling (UniProt P01116). Under physiological conditions, KRAS cycles between an active GTP-bound state and an inactive GDP-bound state to regulate downstream pathways such as MAPK/ERK and PI3K/AKT, which control cell growth, differentiation, and survival (PubMed: 33473105). The G12D mutation, characterized by a glycine-to-aspartic acid substitution at position 12, stabilizes the GTP-bound active form by hindering GTP hydrolysis, leading to constitutive oncogenic signaling (Nature: 618, 159–166). This specific mutation is highly prevalent in human cancers, particularly in over 90% of pancreatic ductal adenocarcinomas and significant portions of colorectal and lung cancers (Cancer Discovery: 12(4), 924-933). While KRAS was long deemed "undruggable" due to its smooth surface and picomolar affinity for GTP, recent breakthroughs have yielded potent G12D-selective inhibitors like MRTX1133 and degraders like ASP3082 (ClinicalTrials.gov: NCT05737706). These therapeutic strategies aim to selectively inhibit the mutant protein while sparing wild-type KRAS, thereby minimizing systemic toxicity and providing a targeted approach for patients with G12D-driven malignancies.

Other names

KRAS proto-oncogene, GTPasep21RASK2K-Ras 2Kirsten rat sarcoma viral oncogene homolog

Non-covalent inhibition of the active (GTP-bound) or inactive (GDP-bound) state of the KRAS G12D mutant protein, or targeted protein degradation via Proteolysis-targeting chimera (PROTAC) technology.