Mutant Kirsten rat sarcoma virus oncogene homolog-derived peptide–Major Histocompatibility Complex (mutant KRAS-pMHC)

Mutant Kirsten rat sarcoma virus oncogene homolog (KRAS)-derived peptide–Major Histocompatibility Complex (pMHC) complexes are neoantigens formed when intracellular mutant KRAS proteins are processed by the proteasome and presented on the cell surface by MHC molecules [1, 3]. KRAS mutations, particularly at codons 12, 13, and 61, are primary drivers in many lethal malignancies, including pancreatic, colorectal, and lung cancers [1, 4]. Because these mutant peptides are absent in normal tissues, the resulting pMHC complexes serve as highly specific targets for the immune system, minimizing the risk of on-target, off-tumor toxicity [2, 3]. Therapeutic interventions targeting these complexes include TCR-engineered T-cell (TCR-T) therapies, which utilize synthetic receptors to recognize specific peptide-HLA combinations, and cancer vaccines designed to enhance the presentation of these neoantigens by professional antigen-presenting cells (APCs) to prime endogenous T-cell responses [1, 2]. Despite their promise, the clinical utility of targeting KRAS-pMHC is limited by the high degree of HLA polymorphism, requiring therapies to be matched to both the specific KRAS mutation and the patient's HLA allele [3, 4]. Additionally, tumor evasion through HLA downregulation or loss of heterozygosity remains a significant therapeutic challenge [1, 4]. Sources: [1] Leidner, R., et al. (2022) NEJM; [2] Pant, S., et al. (2024) Nature Medicine; [3] Tran, E., et al. (2016) NEJM; [4] Bear, A. S., et al. (2020) Cancer Cell.

Other names

KRAS neoantigen-MHC complexMutant KRAS-HLA complexKRAS-derived neoepitope-MHCKRAS-pMHCMutant KRAS-derived peptide-HLA complex

Recognition of the specific mutant peptide-MHC complex by T-cell receptors (TCRs) or TCR-mimetic antibodies, leading to the activation of cytotoxic T-lymphocytes and subsequent lysis of cells presenting the neoantigen.