Mutant HRAS neoantigen peptide-HLA complex

The mutant HRAS neoantigen peptide-HLA complex forms when oncogenic mutations in HRAS, such as those at hotspots G12, G13, or Q61 (analogous to KRAS G12 and NRAS Q61 mutations), generate altered peptides that bind to specific HLA molecules, creating neoepitopes uniquely presented on cancer cell surfaces.[1][2] These complexes are recognized by T cell receptors (TCRs), enabling T cell-mediated immune responses against tumors, as structural studies of similar RAS mutants (e.g., KRAS G12D-HLA-C*08:02, NRAS Q61K/R-HLA-A*01) show how mutant residues form stabilizing interactions like salt bridges with HLA helices, enhancing presentation over wild-type peptides.[1][2][3] Unlike self-peptides, the neoantigen conformation exposes mutant side chains for TCR docking, often via CDR3 loops focusing on the mutation site, promoting selective tumor killing without cross-reactivity to normal tissues.[1][2][4] In cancer, hyperactive HRAS drives oncogenesis through constitutive signaling, but its neoantigens offer immunotherapy targets like TCR-T cells or vaccines.[1][2] No approved drugs directly target this complex, though clinical trials explore TCR therapies against RAS neoantigens, with challenges in HLA restriction and TCR affinity optimization.[1][2]

Other names

HRAS mutant peptide-HLA complexHRAS neoepitope-HLA complex