KRAS mutant peptide-MHC class I complex (mKRAS-pMHC)

The KRAS mutant peptide-MHC class I complex is a tumor-specific neoantigen formed when mutated KRAS proteins (e.g., G12D, G12V, G12C) are processed by the proteasome and the resulting peptide fragments are presented on the cell surface by Major Histocompatibility Complex (MHC) class I molecules (NIH/PubMed, ResearchGate). This complex serves as a critical target for the adaptive immune system, specifically for CD8+ cytotoxic T cells, as it distinguishes malignant cells from healthy tissue expressing wild-type KRAS (NIH/PubMed, Kactus Bio). In cancers such as pancreatic, colorectal, and non-small cell lung cancer, where KRAS mutations are prevalent drivers, these complexes are being exploited as therapeutic targets for novel modalities including TCR-engineered T-cell (TCR-T) therapies, TCR-mimic antibodies, and cancer vaccines (NIH/PubMed, ClinicalTrials.gov). A unique therapeutic strategy involves "haptenated" complexes, where covalent KRAS inhibitors (like sotorasib or divarasib) bind to the mutant protein, creating a drug-modified peptide that is subsequently presented on MHC I (Aethon Therapeutics, AACR Journals). This synthetic neoantigen can be targeted by bispecific T-cell engagers (e.g., AETX-R114, AETX-R302) to overcome resistance to small-molecule inhibitors (Aethon Therapeutics, Nature Communications). Despite its potential, targeting these complexes faces challenges such as low antigen density on the cell surface and the requirement for precise HLA matching between the therapy and the patient (NIH/PubMed, AACR Journals). Furthermore, the risk of cross-reactivity with wild-type KRAS or other RAS family members necessitates high specificity in drug design to avoid off-target toxicity (AACR Journals).

Other names

KRAS neoantigenmKRAS-HLA complexKRAS mutant peptide-HLA complexHaptenated KRAS-MHC complexKRAS G12D-MHC I complexKRAS G12V-MHC I complexKRAS G12C-MHC I complex

T-cell mediated cytotoxicity via TCR-engineered T cells or bispecific T-cell engagers; active immunization via peptide or mRNA vaccines; and hapten-mediated immune targeting following covalent inhibition.