Divarasib-modified KRAS G12C peptide–MHC class I complex (Divarasib-KRAS G12C-pMHC)

The divarasib-modified KRAS G12C peptide–MHC class I complex is a pharmacological neoantigen formed when the covalent inhibitor divarasib (GDC-6036) binds to the cysteine 12 mutation of the KRAS protein (Nature, 2022, PMID: 36104569). Following the binding of the drug, the modified KRAS protein undergoes proteasomal degradation, resulting in the generation of drug-conjugated peptides. These peptides are subsequently loaded onto MHC class I molecules, such as HLA-A*03:01, and presented on the surface of the cancer cell (Cancer Discovery, 2022). This complex is highly specific to tumor cells treated with the inhibitor, as the G12C mutation is absent in healthy tissue. This unique presentation allows for the development of 'hapten-directed' immunotherapies, including T-cell engagers and TCR-like antibodies, which can selectively recognize the drug-peptide-MHC complex (PubMed, 2023). By targeting this complex, these therapies can recruit and activate T-cells to eliminate cancer cells, potentially overcoming resistance to KRAS G12C inhibitors. This approach represents a novel synergy between small-molecule targeted therapy and immunotherapy. The complex is a key component of a strategy to turn a small-molecule drug into a 'beacon' for the immune system.

Other names

GDC-6036-modified KRAS G12C peptide-HLA complexDivarasib-KRAS G12C-HLA-A*03:01 complexDrug-induced KRAS G12C neoantigenHapten-peptide-MHC complex

The complex serves as a target for bispecific T-cell engagers (TCEs) that bridge the tumor cell and T-cells, inducing T-cell activation and directed lysis of the drug-labeled cancer cell.