Kirsten rat sarcoma virus oncogene homolog (KRAS) mutant neoantigen (Mutant KRAS neoantigen)

Kirsten rat sarcoma virus oncogene homolog (KRAS) is a small GTPase that functions as a critical molecular switch in the RAS/MAPK and PI3K/AKT signaling pathways, which regulate cell growth, differentiation, and survival (UniProt P01116). Mutations in the KRAS gene, most commonly at codons 12, 13, or 61, result in a protein that is constitutively locked in the active GTP-bound state, driving uncontrolled cellular proliferation and oncogenesis (Simanshu et al., 2017, Cell). These mutations are prevalent in some of the most lethal cancers, including pancreatic, colorectal, and non-small cell lung cancers. In the context of immunotherapy, mutant KRAS proteins are processed into short peptides, known as neoantigens, and presented on the cell surface by Human Leukocyte Antigen (HLA) molecules (Leidner et al., 2022, N Engl J Med). These mutant KRAS neoantigens are highly tumor-specific, as they are not present in normal tissues, making them ideal targets for antigen-specific T-cell therapies such as TCR-engineered T cells (TCR-T) and cancer vaccines (Bear et al., 2020, J Clin Invest). While small molecule inhibitors like sotorasib and adagrasib directly target the mutant protein (specifically G12C), T-cell based approaches aim to recognize the peptide-HLA complex to induce a targeted immune response against the tumor.

Other names

KRAS mutantp21 rasK-Ras 2Kirsten rat sarcoma virus oncogene homologKRAS G12DKRAS G12VKRAS G12C

Antigen-specific T-cell receptor (TCR) recognition of mutant KRAS peptides presented by HLA molecules, leading to T-cell activation and cytotoxic lysis of tumor cells; or direct inhibition of the mutant KRAS protein's GTPase activity by small molecules.