Kirsten rat sarcoma virus oncogene homolog G12C mutant neoantigen (KRAS G12C neoantigen)

The KRAS G12C mutant neoantigen is a tumor-specific antigen arising from a point mutation in the KRAS gene, where glycine is substituted by cysteine at codon 12. This mutation is a hallmark driver in several malignancies, most notably non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic ductal adenocarcinoma (Nature Reviews Drug Discovery, 2022). As a neoantigen, the mutated protein fragment is processed into peptides and presented on the cell surface by Major Histocompatibility Complex (MHC) molecules, specifically HLA-A*03:01 and HLA-A*11:01. This presentation allows the immune system to distinguish malignant cells from healthy tissue, which expresses only the wild-type KRAS protein. Therapeutic strategies targeting this neoantigen include TCR-engineered T-cell therapies and cancer vaccines designed to elicit a robust, mutation-specific T-cell response (Nature Medicine, 2024). Additionally, the KRAS G12C protein is the target of covalent small-molecule inhibitors that exploit the mutant cysteine to disrupt intracellular signaling. The dual potential for direct pharmacological inhibition and immune-mediated clearance makes the KRAS G12C neoantigen a high-priority target in precision oncology.

Other names

KRAS G12C mutant peptideKRAS G12C-HLA complexKRAS G12C tumor-specific antigenKRAS G12C TSA

The KRAS G12C mutant neoantigen is targeted through the recognition of the mutant peptide-HLA complex by T-cell receptors (TCRs) or TCR-like antibodies, which triggers a cytotoxic immune response against tumor cells (Nature Medicine, 2024). Additionally, the source protein is targeted by covalent small-molecule inhibitors that bind to the cysteine residue at position 12, locking the protein in an inactive state and inhibiting downstream oncogenic signaling (Nature, 2020).