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

Kirsten rat sarcoma virus oncogene homolog (KRAS) is a member of the Ras GTPase family that functions as a critical molecular switch in signal transduction pathways, including the MAPK/ERK and PI3K/AKT/mTOR cascades (UniProt P01116). The G12V mutation, characterized by a glycine-to-valine substitution at codon 12, impairs the protein's ability to hydrolyze GTP, resulting in a constitutively active state that drives autonomous cell growth and survival (PubMed: 33473105). This specific mutation is highly prevalent in pancreatic ductal adenocarcinoma and colorectal cancer, making it a high-priority therapeutic target (NIH NCI). While KRAS was historically deemed undruggable due to its high affinity for GTP and lack of deep binding pockets, recent breakthroughs have produced non-covalent inhibitors like MRTX1133 and multi-RAS inhibitors like RMC-6236 that specifically target the G12V variant or the active state of the protein (PubMed: 34914325). These agents aim to suppress oncogenic signaling and are currently being evaluated in clinical trials to improve outcomes for patients with KRAS G12V-mutant malignancies.

Other names

KRAS proto-oncogene, GTPasep21 proteinK-Ras 2KRAS2RASK2G12V mutant KRAS

Non-covalent inhibition of the KRAS G12V mutant protein, often by binding to the switch II pocket or stabilizing the inactive GDP-bound state, thereby preventing downstream signaling through the MAPK and PI3K pathways.