Sotorasib-modified KRAS G12C peptide-HLA-A3 complex (Sotorasib-KRASG12C-HLA-A3)

The Sotorasib-modified KRAS G12C peptide presented on HLA-A3 supertype pMHC is a novel class of therapeutic target known as a drug-induced neoantigen (DINA). It is formed when the covalent inhibitor Sotorasib (AMG 510) binds to the mutant cysteine residue at position 12 of the KRAS protein [1]. Once the drug-protein adduct is formed, it is processed by the cell's internal machinery into short peptides, which are then loaded onto Major Histocompatibility Complex (MHC) Class I molecules, specifically those of the HLA-A3 supertype (such as HLA-A*03:01), and displayed on the cell surface [1][2]. This complex is highly specific to tumor cells that both harbor the KRAS G12C mutation and have been treated with Sotorasib, making it an ideal target for precision immunotherapy [1]. By using bispecific antibodies or T-cell receptor (TCR) therapies to recognize this drug-modified 'hapten' peptide, researchers aim to overcome resistance to KRAS inhibitors and provide a second hit to cancer cells that have already been sensitized by the small molecule drug [1][3].

Other names

Sotorasib-modified KRAS G12C neoantigenDrug-induced neoantigen (DINA)Sotorasib-haptenated KRAS G12C peptide-MHCAMG 510-modified KRAS G12C pMHCSotorasib-KRAS G12C HLA-A*03:01 complex

The target is recognized by specialized immunotherapies, such as bispecific antibodies or TCR-engineered T-cells, which bind specifically to the Sotorasib-modified peptide presented within the HLA-A3 binding groove to trigger T-cell mediated lysis of the cancer cell [1].