Mutant Kirsten rat sarcoma virus oncogene homolog peptide–Human leukocyte antigen class I complex (Mutant KRAS-HLA-I complex)

Mutant Kirsten rat sarcoma virus oncogene homolog (KRAS) peptide–Human leukocyte antigen (HLA) class I complexes are neoantigens formed when mutated KRAS proteins are processed and presented on the surface of cancer cells (Nature, 2016, 10.1038/nature20117). KRAS is a GTPase that acts as a molecular switch in signaling pathways like MAPK and PI3K, and its mutations (most commonly at codon 12) are primary drivers in pancreatic, colorectal, and lung cancers (Nature Reviews Cancer, 2019, 10.1038/s41568-019-0200-2). These mutant peptides are absent in normal cells, making the pHLA complex a highly specific target for immunotherapies such as T-cell receptor (TCR) engineered T-cells and cancer vaccines (NEJM, 2022, 10.1056/NEJMoa2119662). Therapeutic agents are designed to recognize the specific combination of the mutant peptide and the patient's HLA allele, such as HLA-A*11:01 or HLA-C*08:02 (Science, 2016, 10.1126/science.aah3819). By engaging these complexes, drugs can trigger a potent and selective cytotoxic T-cell response against tumor cells. However, clinical success is often challenged by tumor-mediated HLA downregulation and the requirement for precise HLA matching between the drug and the patient (Cancer Discovery, 2021, 10.1158/2159-8290.CD-20-1083).

Other names

KRAS neoantigen-MHC complexMutant KRAS-pHLA complexKRAS G12D-HLA-A*11:01 complexKRAS G12V-HLA-A*11:01 complexKRAS G12D-HLA-C*08:02 complexmKRAS-HLA-I

T-cell receptor (TCR) mediated recognition of the mutant peptide-HLA complex, leading to the activation of cytotoxic T-lymphocytes and subsequent lysis of the target tumor cell.