Mutated Kirsten rat sarcoma virus oncogene homolog peptide–Major Histocompatibility Complex (KRAS-MHC)

Mutated KRAS peptide–Major Histocompatibility Complex (MHC) complexes are neoantigens formed when mutated KRAS proteins are intracellularly processed into short peptides and presented on the cell surface by MHC molecules. 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, and 61—are primary drivers in pancreatic, colorectal, and lung cancers (Prior et al., 2020, Cancer Research). These mutations result in "non-self" peptides that can be recognized by the immune system when presented by specific Human Leukocyte Antigen (HLA) alleles, such as HLA-A*11:01 or HLA-C*08:02 (Wang et al., 2016, Science). On tumor cells, these complexes serve as targets for cytotoxic T-cells, while on antigen-presenting cells (APCs), they facilitate the priming of the adaptive immune response. Therapeutic approaches targeting these complexes include TCR-engineered T-cell (TCR-T) therapies and neoantigen vaccines, which aim to overcome the historical "undruggability" of KRAS by targeting it at the surface level (Leidner et al., 2022, NEJM). Unlike small-molecule inhibitors that bind the protein's active site, these immunotherapies rely on the specificity of the T-cell receptor for the peptide-MHC interface. This target is highly specific to malignant cells, minimizing off-target effects on healthy tissue expressing wild-type KRAS. However, challenges remain, including tumor immune escape through the downregulation of MHC molecules or the loss of the mutated allele (Pant et al., 2024, Nature Medicine).

Other names

KRAS neoantigen-MHC complexMutated KRAS-HLA complexKRAS-pMHCKRAS-HLA-A*11:01 complexKRAS-HLA-C*08:02 complex

Recognition by T-cell receptors (TCRs) or TCR-like molecules to induce a targeted cytotoxic immune response against cells presenting mutated KRAS fragments.