Kirsten rat sarcoma viral oncogene homolog G12D-mutated protein (KRAS (G12D))

KRAS G12D-mutated protein is a specific oncogenic variant of the small GTPase Kirsten rat sarcoma viral oncogene homolog (KRAS), arising from a glycine-to-aspartic acid substitution at position 12 (G12D)[1][4]. This mutation locks KRAS in the GTP-bound, constitutively active state, leading to persistent downstream signaling through pathways such as PI3K/AKT and MAPK, and thereby promotes uncontrolled cell proliferation, survival, and metabolic reprogramming, most notably in cancers like pancreatic, colorectal, and lung cancer[1][3][4]. The G12D mutation is the most prevalent KRAS alteration in pancreatic adenocarcinoma and is recognized as a major therapeutic target in oncology[2][4]. Recent efforts have identified drugs, such as MRTX1133 and synthetic binding proteins (monobodies), which selectively inhibit KRAS(G12D) by targeting the switch II pocket, preventing effector binding and tumorigenic signaling. Patient selection for these therapies uses KRAS G12D as a biomarker, though resistance mechanisms and systemic effects on normal tissue signaling remain ongoing challenges[4].

Other names

KRAS G12D-mutantKRAS p.G12DKRAS Gly12AspKRAS(G12D)Oncogenic KRAS G12D

Selective binding to the switch II pocket to inhibit interaction of KRAS(G12D) with downstream effectors (e.g., RAF); Interfering with KRAS(G12D)-mediated signal transduction; Blocking GTP-bound active conformation