Kirsten rat sarcoma virus oncogene homolog G12V (KRAS G12V)

Kirsten rat sarcoma virus oncogene homolog (KRAS) G12V is a specific oncogenic mutant of the KRAS protein, a member of the small GTPase family that functions as a critical relay in the RAS/MAPK signaling pathway (UniProt Consortium, 2024). Under normal physiological conditions, KRAS cycles between an active GTP-bound state and an inactive GDP-bound state to regulate essential cellular processes such as proliferation, differentiation, and survival (National Cancer Institute, 2023). The G12V mutation involves a single amino acid substitution of glycine with valine at position 12, which severely impairs the protein's ability to hydrolyze GTP and renders it insensitive to GTPase-activating proteins (GAPs). This results in the protein being constitutively locked in its active, signaling-competent conformation, driving the continuous activation of downstream pathways like RAF-MEK-ERK and PI3K-AKT (Kessler et al., 2020). KRAS G12V is highly prevalent in several lethal cancers, particularly pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer. While KRAS was long deemed undruggable due to its high affinity for GTP and lack of suitable binding pockets, recent breakthroughs have yielded selective inhibitors like RMC-9805 and multi-RAS inhibitors like RMC-6236 that specifically target the mutant protein's active state (Revolution Medicines, 2023). These therapeutic strategies aim to suppress oncogenic signaling and overcome the historical challenges of targeting this central driver of tumorigenesis (ClinicalTrials.gov, 2024).

Other names

KRAS G12Vp.Gly12ValKRAS2RASK2Kirsten rat sarcoma 2 viral oncogene homologp21 protein

Selective inhibition of the KRAS G12V mutant protein by binding to the active (GTP-bound) or inactive (GDP-bound) state, thereby blocking downstream signaling through the MAPK and PI3K pathways.