Mutant Kirsten rat sarcoma virus oncogene homolog (KRAS) neoantigen-MHC class I complex (Mutant KRAS-MHC I)

Mutant KRAS-derived peptide antigens presented on MHC class I molecules are highly specific tumor neoantigens formed when mutated KRAS proteins are processed and displayed on the surface of cancer cells. KRAS mutations, most commonly at codon 12 (e.g., G12D, G12V, G12C), are primary drivers in aggressive malignancies such as pancreatic, colorectal, and lung cancers (Simanshu et al., 2017, Cell). These mutations result in unique amino acid sequences that, when presented by specific Human Leukocyte Antigen (HLA) alleles, can be recognized by the T-cell receptor (TCR) of cytotoxic T-cells. Unlike wild-type KRAS, these mutant peptide-MHC complexes are not present on normal tissues, making them exceptionally attractive targets for precision immunotherapy with minimal off-target risks (Bear et al., 2020, Cancer Cell). Current therapeutic strategies include TCR-engineered T-cell (TCR-T) therapies, which have shown clinical efficacy in treating metastatic colorectal and pancreatic cancers by targeting specific KRAS-HLA combinations like G12D presented by HLA-C*08:02 (Leidner et al., 2022, NEJM). Additionally, neoantigen vaccines and TCR-like bispecific antibodies are being developed to stimulate or simulate an immune response against these specific complexes. The effectiveness of these treatments is contingent upon the patient's HLA profile and the tumor's ability to maintain antigen presentation machinery. This target represents a shift toward personalized oncology, where the therapy is tailored to both the genetic mutation of the tumor and the immunological background of the patient.

Other names

KRAS neoepitopeMutant KRAS peptide-HLA complexKRAS G12D-HLA complexKRAS G12V-HLA complexKRAS G12C-HLA complex

T-cell receptor (TCR) mediated recognition and activation of cytotoxic T-lymphocytes leading to tumor cell lysis.