Kirsten rat sarcoma virus oncogene homolog (KRAS) mutant neoantigens (Mutant KRAS neoantigens)

Mutant KRAS neoantigens are tumor-specific peptide fragments derived from somatic mutations in the Kirsten rat sarcoma virus oncogene homolog (KRAS) protein, a GTPase central to cell signaling (Prior et al., 2020, Cancer Research). In many high-prevalence cancers, such as pancreatic and colorectal adenocarcinomas, specific point mutations (e.g., G12D, G12V) render the KRAS protein constitutively active, driving malignant transformation. These mutations create unique amino acid sequences that are absent in normal tissues, making them ideal targets for the immune system when presented as neoepitopes on Major Histocompatibility Complex (MHC) molecules. Therapeutic strategies targeting these neoantigens include cancer vaccines, such as mRNA-5671 and ELI-002, which aim to stimulate endogenous T-cell responses (Pant et al., 2024, Nature Medicine). Additionally, adoptive cell therapies using T-cell receptors (TCRs) engineered to recognize specific KRAS-mutant peptides have shown clinical efficacy in treating advanced solid tumors (Leidner et al., 2022, NEJM). Because these targets are strictly tumor-specific, they offer a high therapeutic index with a reduced risk of on-target, off-tumor toxicity compared to traditional therapies. However, challenges such as HLA restriction and tumor-mediated immune evasion via HLA downregulation remain significant hurdles in the broad application of these immunotherapies.

Other names

KRAS neoepitopesMutant KRAS-derived peptidesKRAS G12D/G12V/G12C neoantigensmKRAS antigens

Induction of tumor-specific T-cell immunity through the presentation of mutant KRAS peptides on MHC molecules, leading to selective lysis of KRAS-mutant cancer cells (Pant et al., 2024, Nature Medicine).