Mutant Kirsten rat sarcoma virus oncogene homolog (KRAS) neoantigen peptide–Major Histocompatibility Complex (MHC) class I complex (Mutant KRAS-pMHC)

Mutant KRAS neoantigen peptide–MHC class I complexes are cell-surface structures consisting of a mutated KRAS peptide fragment bound within the groove of a Major Histocompatibility Complex (MHC) class I molecule (UniProt: P01116). KRAS is a GTPase that acts as a molecular switch in signaling pathways like MAPK and PI3K, and its mutations (e.g., G12D, G12V, G12C) are primary drivers in pancreatic, colorectal, and lung cancers (PubMed: 32060151). These mutations generate unique amino acid sequences, known as neoantigens, which are processed by the proteasome and presented on the cell surface by Human Leukocyte Antigen (HLA) molecules (Nature Reviews Cancer: 10.1038/s41568-021-00439-z). Because these neoantigens are absent in healthy tissues, the mutant KRAS-pMHC complex serves as a highly specific target for immunotherapy, allowing the immune system to recognize and eliminate tumor cells (NCI: cancer.gov). Therapeutic strategies targeting these complexes include TCR-engineered T-cell (TCR-T) therapies, bispecific T-cell engagers, and neoantigen vaccines (Nature Medicine: 10.1038/s41591-023-02760-3). Clinical success has been demonstrated with TCR-T cells recognizing KRAS G12D presented by HLA-C*08:02, leading to significant tumor regression in patients with metastatic colorectal cancer (NEJM: 10.1056/NEJMoa2203119). However, therapeutic efficacy can be limited by tumor escape mechanisms such as HLA downregulation or loss of heterozygosity (Nature: 10.1038/s41586-019-1469-z).

Other names

Mutant KRAS-HLA complexKRAS neoantigen-MHC complexKRAS G12D-HLA-A*11:01 complexKRAS G12V-HLA-A*02:01 complexKRAS G12D-HLA-C*08:02 complexKRAS G12C-HLA-A*03:01 complex

Recognition of the specific mutant KRAS peptide presented on HLA molecules by engineered T-cell receptors (TCRs) or TCR-mimetic antibodies, which triggers T-cell activation, cytokine release, and direct lysis of the target tumor cells.