Mutant KRAS peptide-Major Histocompatibility Complex (Mutant KRAS-pMHC)

Mutant KRAS-derived peptide–MHC (pMHC) complexes are cell-surface structures composed of a mutated KRAS peptide fragment bound to a Major Histocompatibility Complex (MHC) molecule, typically HLA Class I. KRAS is a GTPase that normally regulates cell growth, but specific mutations at codons 12, 13, or 61 lead to constitutive signaling and are hallmark drivers in pancreatic, colorectal, and lung cancers (Simanshu et al., 2017, Cell). These mutations result in the production of neoantigens—peptides not found in the normal proteome—which are processed by the proteasome and presented on the cell surface by MHC molecules for surveillance by the immune system (Bear et al., 2020, Cancer Discovery). Because these complexes are unique to tumor cells, they serve as highly specific targets for immunotherapies, including T-cell receptor (TCR) engineered T-cells, bispecific antibodies, and neoantigen vaccines (Leidner et al., 2022, NEJM). Therapeutic strategies aim to leverage the high specificity of the mutant peptide to induce a potent cytotoxic T-cell response while sparing healthy tissues that express only wild-type KRAS.

Other names

KRAS neoantigen-HLA complexMutant KRAS-HLA complexKRAS-derived neoepitope-MHCMutant Kirsten rat sarcoma virus oncogene homolog peptide-MHC

T-cell receptor (TCR) binding and activation, Induction of antigen-specific cytotoxic T-lymphocyte response, Immune-mediated tumor cell lysis