Kirsten rat sarcoma viral oncogene homolog G12V mutant (KRAS G12V) (KRAS G12V)

KRAS G12V is a specific oncogenic mutant of the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein, a small GTPase that acts as a molecular switch in cell signaling (Source: Merck, 2025). The G12V mutation involves a substitution of glycine with valine at position 12, which impairs the protein's intrinsic GTPase activity and renders it resistant to GTPase-activating proteins (GAPs) (Source: PatSnap, 2024). This results in the protein being constitutively locked in an active, GTP-bound state, perpetually driving downstream signaling pathways such as MAPK/ERK and PI3K/AKT that promote uncontrolled cell proliferation and survival (Source: NIH, 2024). KRAS G12V is highly prevalent in several aggressive malignancies, including approximately 30% of pancreatic ductal adenocarcinomas, 22% of colorectal cancers, and 22% of lung adenocarcinomas (Source: UNC Lineberger, 2025). Historically considered "undruggable," recent therapeutic strategies have emerged, including allele-selective small molecule inhibitors, tri-complex inhibitors that target the active state, and neoantigen-based immunotherapies like vaccines and TCR-T cells (Source: BMJ, 2025; OncoDaily, 2025). Clinical development is focused on overcoming resistance and achieving selectivity over the wild-type protein to minimize systemic toxicity (Source: NIH, 2025).

Other names

KRAS G12VKRAS p.G12VKRAS p.Gly12ValKirsten rat sarcoma viral oncogene homolog G12VGTPase KRas G12V

Direct inhibition of the mutant protein by stabilizing the inactive GDP-bound conformation or sterically blocking effector interactions in the active GTP-bound state via tri-complex formation; also targeted via RNA interference and neoantigen-directed immunotherapy.