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

KRAS G12V is a specific oncogenic mutant of the Kirsten rat sarcoma virus oncogene homolog (KRAS), a small GTPase that functions as a critical molecular switch in cellular signaling pathways. The G12V mutation involves a substitution of glycine with valine at codon 12, which severely impairs the protein's intrinsic GTPase activity and renders it resistant to GTPase-activating proteins (GAPs) (patsnap.com, 2024). Consequently, the protein remains constitutively locked in its active, GTP-bound state, leading to persistent activation of downstream effectors such as the MAPK/ERK and PI3K/AKT pathways (nih.gov, 2026). This dysregulated signaling drives hallmark cancer processes, including uncontrolled cell proliferation, survival, and metabolic reprogramming (oncokb.org, 2024). KRAS G12V is highly prevalent in several aggressive malignancies, most notably pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer (bmj.com, 2025). Historically considered undruggable due to its high affinity for GTP and lack of deep binding pockets, recent therapeutic advances have introduced novel strategies such as active-state tri-complex inhibitors and mutation-selective RNA interference (unclineberger.org, 2025). Additionally, the G12V mutation creates a unique neoantigen, making it a target for personalized immunotherapies including vaccines and TCR-engineered T-cell therapies (ucbraid.org, 2026).

Other names

KRAS G12VGTPase KRas G12VK-Ras G12Vp.Gly12Val mutantKirsten rat sarcoma 2 viral oncogene homolog G12V

Inhibition of the active GTP-bound state through tri-complex formation with cyclophilin A; stabilization of the inactive GDP-bound state; RNA interference-mediated gene silencing; and induction of T-cell responses against the G12V neoantigen (patsnap.com, 2024; unclineberger.org, 2025).