Sotorasib-modified KRAS G12C peptide-Major Histocompatibility Complex class I (Sotorasib-KRAS G12C-MHC I)

The Sotorasib-modified KRAS G12C peptide-Major Histocompatibility Complex class I (MHC I) complex is a drug-induced neoantigen (DINA) that forms on the surface of cancer cells following treatment with the covalent inhibitor Sotorasib [1]. Sotorasib specifically targets the cysteine residue at position 12 of the mutant KRAS G12C protein, forming a stable covalent adduct [2]. This modified protein is subsequently processed by the cellular proteasome into smaller peptides, which are then loaded onto MHC I molecules and presented on the plasma membrane [1]. This complex serves as a highly specific marker for tumor cells, as it requires both the presence of the KRAS G12C mutation and the successful binding of the drug [3]. Emerging therapeutic strategies, including TCR-engineered T-cells and bispecific T-cell engagers, are being developed to recognize this specific haptenated peptide-MHC complex to trigger an immune response against the tumor [1]. This approach potentially addresses resistance to KRAS inhibitors by providing a secondary, immune-mediated mechanism of action [2].

Other names

Sotorasib-haptenated KRAS G12C peptide-HLA complexAMG 510-modified KRAS G12C neoantigenDrug-induced neoantigen (DINA)Sotorasib-KRAS G12C-MHC adduct

Sotorasib covalently binds to the KRAS G12C mutant protein; the resulting drug-peptide adduct is processed and presented by MHC I, creating a neoantigen that can be targeted by engineered T-cells or antibodies to induce tumor cell lysis [1][2].