GTPase KRAS (G12V mutant) (KRAS G12V)

KRAS (Kirsten rat sarcoma virus oncogene homolog) is a small GTPase that functions as a critical molecular switch in the cell, relaying signals from cell surface receptors to the nucleus to regulate growth, differentiation, and survival (UniProt P01116). The G12V mutation involves a substitution of glycine with valine at position 12, which sterically hinders the GAP-mediated hydrolysis of GTP, locking the protein in a constitutively active, GTP-bound state (Nature Reviews Cancer, 2021). This persistent activation drives oncogenic signaling through the MAPK/ERK and PI3K/AKT pathways, contributing significantly to the pathogenesis of various malignancies, most notably pancreatic, colorectal, and lung cancers (Nature Reviews Drug Discovery, 2020). Historically considered undruggable, KRAS G12V is now a focal point for drug development, including the design of state-selective small molecule inhibitors and neoantigen-based immunotherapies (Cell, 2017). Therapeutic strategies include vaccines and TCR-T cell therapies that specifically target the mutant peptide sequence presented on the cell surface by major histocompatibility complex (MHC) molecules (ClinicalTrials.gov NCT04853017). Targeting KRAS G12V aims to inhibit uncontrolled cell proliferation and survival in mutant-bearing tumors while sparing healthy cells expressing the wild-type protein (ClinicalTrials.gov NCT05379985).

Other names

Kirsten rat sarcoma virus oncogene homolog (G12V)p21 Ras (G12V)KRAS G12V neoantigenKRAS G12V mutant peptide

Non-covalent inhibition of the active (GTP-bound) state of KRAS, disruption of effector protein binding, or induction of T-cell mediated cytotoxicity against cells presenting the mutant peptide neoantigen.