Kirsten rat sarcoma virus oncogene homolog (KRAS) G12V mutant peptide–Major Histocompatibility Complex (MHC) class I complex (KRAS G12V-MHC I)

The Kirsten rat sarcoma virus oncogene homolog (KRAS) G12V mutant peptide–Major Histocompatibility Complex (MHC) class I complex is a tumor-specific neoantigen presented on the surface of malignant cells (Leidner et al., 2022, NEJM). KRAS is a member of the RAS GTPase family that regulates cell signaling pathways involved in growth and survival, such as the MAPK/ERK pathway (Simanshu et al., 2017, Cell). The G12V mutation involves a substitution of glycine with valine at position 12, leading to a constitutively active protein that drives oncogenesis in various cancers, including pancreatic, colorectal, and lung adenocarcinomas (Bear et al., 2020, Cancer Discovery). Intracellular processing of the mutant KRAS protein by the proteasome generates specific peptides containing the G12V mutation, which are then loaded onto MHC class I molecules for presentation to the immune system. This complex is a primary target for T-cell-based immunotherapies because the mutant epitope is absent in normal tissues, providing a high degree of tumor specificity. Therapeutic approaches currently under investigation include T-cell receptor (TCR) engineered T-cells and vaccines like ELI-002 designed to elicit a cytotoxic T-lymphocyte response (Pantalion et al., 2024, Nature Medicine). Recognition of this complex by CD8+ T-cells triggers the release of cytotoxic granules, leading to the targeted destruction of the KRAS-mutant tumor cell. However, challenges such as HLA restriction and the potential for tumor immune escape through MHC downregulation remain significant hurdles in clinical development.

Other names

KRAS G12V-HLA complexKRAS G12V neoantigenKRAS G12V-MHC class I complexKRAS G12V-HLA-A*02:01

Recognition of the peptide-MHC complex by specific T-cell receptors (TCRs) on CD8+ T-cells, leading to T-cell activation and subsequent lysis of the tumor cell.