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

Mutant KRAS-derived peptide–HLA class I complexes are cell-surface neoantigens formed when mutated KRAS proteins are processed by the proteasome and the resulting mutant peptides are presented by Human Leukocyte Antigen (HLA) class I molecules (PubMed: 34161761). KRAS is a GTPase that acts as a molecular switch in signaling pathways like MAPK and PI3K, and its mutations—most commonly at codons 12, 13, or 61—are primary drivers in pancreatic, colorectal, and lung cancers (NIH: PDQ Cancer Genetics). These complexes are highly tumor-specific because the mutant peptide sequence is absent in normal tissues, making them ideal targets for T-cell receptor (TCR)-based therapies and vaccines (Nature: 10.1038/s41586-022-04485-1). Therapeutic interventions, such as TCR-engineered T-cells (TCR-T) or bispecific T-cell engagers, are designed to recognize the unique spatial and chemical signature of the mutant peptide nestled within the HLA groove. Clinical development focuses on specific pairings, such as KRAS G12D presented by HLA-A*11:01 or HLA-C*08:02, to ensure high affinity and specificity. Despite their promise, challenges include the high polymorphism of HLA alleles across the human population and the potential for tumor immune escape through HLA downregulation or loss of heterozygosity. Successful targeting of these complexes represents a significant shift in oncology, moving from direct inhibition of the intracellular KRAS protein to leveraging the immune system to eliminate cells expressing its mutant fragments.

Other names

KRAS neoantigen-HLA complexMutant KRAS-MHC class I complexKRAS G12D-HLA-A*11:01 complexKRAS G12V-HLA-A*02:01 complexKRAS G12R-HLA complexKRAS G12D-HLA-C*08:02 complex

Engineered T-cell receptors or antibodies bind specifically to the mutant KRAS peptide presented in the HLA class I groove, triggering T-cell activation and direct lysis of the tumor cell.