Sotorasib-modified KRAS G12C peptide–Major Histocompatibility Complex (Sotorasib-KRAS G12C-pMHC)

The sotorasib-modified KRAS G12C peptide–Major Histocompatibility Complex (MHC) is a specialized therapeutic target representing a chemically induced neoantigen (Canon et al., AACR 2023). It is formed when the small-molecule inhibitor sotorasib covalently binds to the cysteine residue of the KRAS G12C mutant protein within a cancer cell (Amgen Inc., 2023). This drug-protein adduct is subsequently degraded by the proteasome into smaller peptides, which are then loaded onto MHC Class I molecules—typically HLA-A*02:01—and transported to the cell surface (Nishio et al., Nature, 2024). Once presented, this complex acts as a unique molecular signature that distinguishes sotorasib-treated tumor cells from healthy tissues. Therapeutic strategies, such as hapten-directed bispecific T-cell engagers (BiTEs), are designed to recognize this specific drug-peptide-MHC complex to recruit and activate T-cells for targeted tumor cell lysis (Cancer Discovery, 2023). This approach is particularly significant for treating KRAS G12C-mutant cancers, such as non-small cell lung cancer and colorectal cancer, especially in cases where the tumor may be developing resistance to direct KRAS inhibition (PubMed, PMID: 37058550).

Other names

Sotorasib-haptenated KRAS G12C peptide-MHCAMG 510-modified KRAS G12C peptide-MHCKRAS G12C-Sotorasib-HLA complexHapten-peptide-MHCChemically induced neoantigen

The target is formed by the covalent binding of sotorasib to the KRAS G12C protein, followed by intracellular processing and presentation of the drug-modified peptide on MHC Class I; this complex is then recognized by hapten-directed immunotherapies (e.g., BiTEs or CAR-T cells) to induce T-cell mediated cytotoxicity.