Kirsten rat sarcoma virus oncogene homolog G12V mutation-derived peptide presented on Major Histocompatibility Complex (KRAS G12V-MHC) (KRAS G12V-MHC)

The Kirsten rat sarcoma virus oncogene homolog (KRAS) G12V-derived peptide presented on the Major Histocompatibility Complex (MHC) is a tumor-specific neoantigen resulting from a common missense mutation in the KRAS proto-oncogene (Leidner et al., 2022, NEJM). KRAS is a small GTPase that cycles between active and inactive states to regulate cell proliferation; the G12V mutation stabilizes the active GTP-bound form, driving oncogenic signaling in malignancies such as pancreatic ductal adenocarcinoma and colorectal cancer (Wang et al., 2021, Frontiers in Immunology). Because this mutant peptide is exclusively expressed by tumor cells and not by healthy tissues, it serves as a highly selective target for precision immunotherapies, including TCR-engineered T-cell (TCR-T) therapies and neoantigen vaccines (Elicio Therapeutics, 2024). These therapies, such as the ELI-002 vaccine, are designed to stimulate or provide T-cells that specifically recognize the KRAS G12V peptide in the context of specific HLA alleles, such as HLA-A*11:01 or HLA-A*02:01 (Pant et al., 2024, Nature Medicine). By targeting this complex, the immune system can selectively destroy cancer cells while sparing normal cells that express the wild-type KRAS protein. However, the effectiveness of these treatments can be challenged by the loss of MHC expression on tumor cells, which allows for immune evasion, and the potential for off-target toxicities if the therapeutic agent cross-reacts with similar peptides (Simanshu et al., 2017, Cell).

Other names

KRAS G12V neoantigenKRAS G12V pMHC complexKRAS G12V-HLA complexKRAS G12V-HLA-A*11:01 complex

Targeted T-cell activation and cytotoxicity through the specific recognition of the mutant KRAS G12V peptide presented by MHC molecules on the surface of tumor cells.