RAS neoantigens

RAS neoantigens are novel peptide epitopes generated from somatic mutations in the RAS family oncogenes (KRAS, NRAS, HRAS), most commonly at glycine 12, glycine 13, or glutamine 61, which alter protein sequences and produce immunogenic fragments presented by HLA class I molecules on cancer cell surfaces[1][2][3]. These neoantigens drive aberrant MAPK signaling that promotes uncontrolled cell proliferation and survival in various cancers, including ~5-26% of hematologic malignancies like AML, ALL, and lymphomas, as well as solid tumors[1]. Unlike wild-type RAS peptides, mutant versions evade central tolerance, making them ideal for T cell-mediated tumor recognition and eliciting spontaneous or therapeutic antitumor immunity[2][4]. Therapeutic strategies exploit this by developing bispecific antibodies, such as single-chain diabodies, that bind mutant RAS-HLA complexes (e.g., G12V-HLA-A*03) and engage CD3 on T cells to induce potent cytotoxicity even at low neoantigen densities[2][3]. RAS neoantigens represent shared or public targets in mutation-defined patient subsets, offering precision immunotherapy advantages over small molecules, which struggle with intracellular RAS, though challenges include variable presentation efficiency and HLA restriction[1][6].

Other names

mutant RAS peptidesRAS mutation-derived neoantigensRAS peptide-HLA complexes

T cell activation and redirected cytotoxicity against cells presenting mutant RAS peptide-HLA complexes, binding specifically to mutant (not wild-type) RAS peptides without cross-reactivity