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

KRAS G12V is a mutant isoform of the Kirsten rat sarcoma virus oncogene homolog, a small GTPase that acts as a molecular switch in cell signaling (UniProt P01116). The G12V mutation involves a substitution of glycine with valine at position 12, which impairs the intrinsic GTPase activity and confers resistance to GTPase-activating proteins (GAPs), locking the protein in a constitutively active, GTP-bound state (PubMed: 34534465). This persistent activation drives downstream signaling through the MAPK/ERK and PI3K/AKT pathways, promoting uncontrolled cell proliferation and survival in various cancers, most notably pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer (OncoKB). Historically considered undruggable, recent therapeutic strategies have introduced RAS-multi inhibitors like RMC-6236, which target the active (ON) state of the protein through a molecular glue mechanism involving Cyclophilin A (ClinicalTrials.gov NCT05379985). Other emerging modalities include mutation-specific vaccines, RNA interference, and TCR-T cell therapies designed to selectively target the G12V neoantigen while sparing wild-type signaling (PubMed: 37287989). The prevalence of KRAS G12V is particularly high in gastrointestinal malignancies, where it serves as a poor prognostic factor and a driver of resistance to EGFR-targeted therapies (PubMed: 28572459).

Other names

KRAS p.Gly12ValKRAS p.G12VKRAS*G12VK-Ras 2Kirsten rat sarcoma 2 viral oncogene homologKRAS proto-oncogene, GTPase

Non-covalent inhibition of the active (GTP-bound) state of the KRAS protein, often utilizing a molecular glue mechanism to form a ternary complex with chaperone proteins like Cyclophilin A, thereby preventing interaction with downstream effectors (PubMed: 34534465; ClinicalTrials.gov NCT05379985).