Drug-modified KRAS G12C peptide-MHC complex (KRAS G12C-drug-pMHC) (KRAS G12C-drug-pMHC)

The drug-modified KRAS G12C peptide-MHC complex is a novel therapeutic target formed when covalent inhibitors, such as sotorasib or adagrasib, bind to the cysteine residue of the KRAS G12C mutant protein [1]. Once the drug is covalently attached, the protein is degraded by the cellular proteasome into smaller peptides, including the drug-conjugated fragment [1, 2]. This modified peptide is then transported to the endoplasmic reticulum and loaded onto Major Histocompatibility Complex (MHC) Class I molecules for presentation on the cell surface [1]. This creates a unique "haptenated" neoantigen that is absent in normal cells, as it requires both the specific KRAS G12C mutation and the presence of the covalent drug [1, 3]. Immunotherapies, such as bispecific T-cell engagers (BiTEs) or CAR-T cells, can be engineered to recognize this specific drug-peptide-MHC complex, effectively turning the small-molecule inhibitor into a beacon for immune-mediated destruction [1]. This strategy aims to overcome resistance to KRAS inhibitors by providing a secondary, independent mechanism of tumor cell killing [2, 3]. The specificity of this target is defined by the combination of the mutant peptide sequence, the chemical structure of the drug, and the specific HLA allele presenting the complex [1]. This approach represents a paradigm shift in oncology, merging the fields of targeted small-molecule therapy and personalized immunotherapy [1, 2].

Other names

Hapten-peptide-MHCDrug-conjugated KRAS G12C neoantigenSotorasib-modified KRAS G12C peptide-HLA complexAdagrasib-modified KRAS G12C peptide-HLA complexDrug-peptide-MHC complex

Covalent modification of KRAS G12C followed by MHC-I presentation of the drug-peptide adduct, enabling recognition by T-cell engagers or CAR-T cells [1].