KRAS-derived neoantigen peptides presented on MHC class I (KRAS neoantigen-MHC I)

KRAS-derived neoantigen peptides presented on MHC class I molecules are highly specific tumor antigens that result from common driver mutations in the KRAS oncogene, such as G12D, G12V, and G12C (Bear et al., 2020, Cancer Cell; PMID: 32649884). These mutations are frequently found in high-mortality cancers, including pancreatic, colorectal, and lung adenocarcinomas. In these cells, the mutant KRAS protein is degraded by the proteasome into short peptides, which are then transported into the endoplasmic reticulum and loaded onto Major Histocompatibility Complex (MHC) class I molecules for surface display. Because these mutant peptides are not expressed in healthy tissues, they provide a unique window for the immune system to distinguish malignant cells from normal ones. Therapeutic interventions targeting these complexes include T-cell receptor (TCR) engineered T-cell therapies and neoantigen-based vaccines like ELI-002 (Pant et al., 2024, Nature Medicine; PMID: 38200214). These therapies rely on the precise recognition of the peptide-MHC complex by T-cells to induce a targeted cytotoxic response. The clinical utility of these targets is highly dependent on the patient's specific HLA genotype, as different MHC alleles present different KRAS-derived peptides (Wang et al., 2016, NEJM; PMID: 27959684). While these targets offer high specificity and reduced risk of off-target toxicity in healthy tissues, therapeutic efficacy can be limited by tumor-mediated downregulation of MHC molecules or other immune evasion mechanisms (Leidner et al., 2022, NEJM; PMID: 35648549).

Other names

KRAS neoepitope-HLA complexMutant KRAS-MHC IKRAS-mutant peptide-MHC complexKRAS-derived neoantigen-HLA-I complex

Recognition of mutant KRAS peptides in the context of MHC class I by T-cell receptors (TCRs) or TCR-mimetic molecules, leading to cytotoxic T-lymphocyte (CTL) activation and tumor cell lysis.