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

The Sotorasib-modified KRAS G12C-Major Histocompatibility Complex Class I (MHC I) complex is a drug-induced neoantigen (DINA) that forms when the covalent inhibitor sotorasib (AMG 510) binds to the mutant cysteine residue of the KRAS G12C protein (Nishikawa et al., 2023, Cancer Discovery). Following this binding, the modified protein is degraded by the proteasome into peptides, including those containing the sotorasib-cysteine adduct, which are then loaded onto MHC I molecules and presented on the cell surface (Zhang et al., 2022, Nature). This complex is highly specific to tumor cells that express the KRAS G12C mutation and have been exposed to sotorasib, making it an ideal target for precision immunotherapy. Research has demonstrated that bispecific antibodies can be engineered to recognize this unique hapten-peptide-MHC structure, facilitating T-cell-mediated destruction of the cancer cells. This strategy is particularly relevant for overcoming resistance to direct KRAS G12C inhibition, as it targets the presence of the mutant protein rather than its signaling activity. The complex is primarily associated with KRAS G12C-mutant non-small cell lung cancer and colorectal cancer. By leveraging the immune system to recognize drug-modified proteins, this target represents a novel frontier in combining small-molecule therapy with immunotherapy.

Other names

Sotorasib-haptenated KRAS G12C-MHC complexAMG 510-modified KRAS G12C-HLA complexDrug-induced neoantigen (DINA) of KRAS G12CSotorasib-peptide-MHC complex

The complex acts as a drug-induced neoantigen (DINA) where sotorasib serves as a hapten; it is targeted by engineered bispecific antibodies or T-cell receptors that bridge the drug-modified peptide-MHC to T-cells, inducing T-cell mediated cytotoxicity against KRAS G12C-mutant cells.