KRAS G12C peptide-Major Histocompatibility Complex neoantigen (KRAS G12C-pMHC)

The KRAS G12C peptide-MHC neoantigen is a tumor-specific surface complex formed by the presentation of mutant KRAS protein fragments on Major Histocompatibility Complex (MHC) molecules [1, 10]. KRAS is a GTPase that, when mutated at glycine 12 to cysteine (G12C), acts as a driver of oncogenesis in various cancers, including lung and colorectal [11, 16]. While intracellular KRAS is difficult to target with antibodies, its degradation products (peptides) are displayed on the cell surface by MHC Class I, creating a "neoantigen" that can be recognized by the immune system [2, 14]. Recent therapeutic strategies involve "haptenated" neoantigens, where covalent KRAS G12C inhibitors (like sotorasib or adagrasib) bind to the mutant cysteine, creating a unique drug-peptide-MHC complex [1, 8]. This complex can be targeted by bispecific T-cell engagers (BiTEs), TCR-engineered T cells (TCR-T), or radioligands, providing a way to kill cancer cells that have become resistant to direct KRAS inhibition [6, 9, 15]. These therapies offer a highly specific approach to cancer treatment by combining the precision of targeted small molecules with the potency of the immune system [4, 16].

Other names

KRAS G12C neoantigenKRAS G12C-HLA complexHaptenated KRAS G12C neoantigenKRAS G12C-pMHC complexMutant KRAS G12C peptide-MHC

Drugs targeting this neoantigen function through T-cell engagement (bispecific antibodies), adoptive cell transfer (TCR-T), or targeted radioligand therapy to induce selective cytotoxicity against cancer cells presenting the mutant KRAS peptide on their surface [6, 10, 15].