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

Mutated KRAS peptide–MHC complexes are tumor-specific neoantigens presented on the surface of cancer cells, formed when intracellular mutant KRAS proteins (such as G12D, G12V, or G12C) are processed into short peptides and loaded onto Major Histocompatibility Complex (MHC) molecules [1.1.2, 1.4.4]. Because these mutations are absent in healthy tissues, these complexes serve as highly specific targets for immunotherapies, including T-cell receptor (TCR) engineered T-cells, bispecific T-cell engagers (TCEs), and cancer vaccines [1.1.1, 1.5.4]. Recognition of these complexes by the immune system triggers a targeted cytotoxic response, allowing for the elimination of tumor cells while sparing normal tissue [1.1.2, 1.2.1]. This approach effectively bypasses the historical undruggability of the KRAS protein by targeting its processed fragments on the cell exterior [1.1.2, 1.5.3]. However, the efficacy of these therapies is highly dependent on the patient's specific HLA genotype and the level of MHC expression on the tumor surface [1.1.3, 1.2.4]. Additionally, novel strategies are exploring haptenated complexes, where covalent inhibitors like sotorasib modify the KRAS peptide within the MHC to create a unique chemical epitope for antibody targeting [1.3.1, 1.5.3].

Other names

KRAS neoantigen-HLA complexKRAS mutant peptide-MHCmKRAS-pMHCKRAS-HLA complexHaptenated KRAS-MHC

T-cell mediated cytotoxicity via TCR or TCR-mimic recognition of the mutant peptide-MHC complex