Mutant RAS-derived peptide-Major Histocompatibility Complex (Mutant RAS-pMHC)

Mutant RAS-derived peptides presented on the Major Histocompatibility Complex (MHC) are highly specific tumor neoantigens resulting from somatic mutations in the KRAS, NRAS, or HRAS genes (PMID: 31515346). These mutations are prevalent in several aggressive cancers, including pancreatic, colorectal, and lung adenocarcinomas (PubMed: 35653311). When the mutant RAS protein is degraded by the cellular proteasome, the resulting mutant peptides are loaded onto MHC molecules and displayed on the cell surface for surveillance by T cells (NIH: PMC6853114). Since these mutant sequences are absent in healthy tissue, the mutant RAS-pMHC complex serves as an ideal target for immunotherapy, offering a high degree of tumor specificity (PMID: 27959684). Therapeutic modalities currently in development include TCR-engineered T-cell (TCR-T) therapies, such as AFNT-211, and neoantigen vaccines like ELI-002 (NCT04853017). These approaches aim to overcome the historical difficulty of targeting RAS directly by instead targeting the unique fingerprint the mutation leaves on the cell surface. The success of these therapies often depends on the patient's specific HLA type and the presence of the corresponding RAS mutation. This target represents a cornerstone of personalized oncology and the next generation of precision immunotherapies.

Other names

KRAS neoantigenRAS neoepitopeMutant RAS-HLA complexRAS-derived neoantigenMutant RAS-pMHC

The mechanism involves the recognition of the mutant peptide-MHC complex by specific T-cell receptors (TCRs) on the surface of engineered or endogenous T cells. This binding event triggers a signaling cascade within the T cell, leading to the release of cytotoxic granules (perforin and granzymes) and cytokines (IFN-gamma, TNF-alpha), which ultimately induce apoptosis in the RAS-mutant tumor cell (PMID: 35653311, PMID: 27959684).