KRAS mutation-derived peptide-HLA class I complex (KRAS-pMHC)

The KRAS mutant peptide-HLA class I complex is a tumor-specific neoantigen formed when mutated KRAS proteins are processed and presented on the surface of malignant cells. KRAS is a GTPase that acts as a critical molecular switch in the RAS/MAPK and PI3K/AKT signaling pathways, which govern cell growth, differentiation, and survival (Simanshu et al., Cell 2017). Mutations in the KRAS gene, particularly at codons 12, 13, and 61, are among the most common oncogenic drivers, occurring in the majority of pancreatic cancers and a significant portion of colorectal and lung cancers (Waters et al., Cold Spring Harb Perspect Med 2018). These mutations result in the presentation of unique peptides by Human Leukocyte Antigen (HLA) class I molecules, which can be recognized by the T-cell receptor (TCR) of cytotoxic T-cells. Because these mutant peptides are absent in normal tissues, the KRAS-pMHC complex serves as a highly specific target for immunotherapies such as TCR-engineered T-cell (TCR-T) therapy and neoantigen vaccines (Leidner et al., N Engl J Med 2022). However, the therapeutic application is complicated by the diversity of HLA alleles, as each therapy must be specific to both the KRAS mutation and the patient's HLA type. Furthermore, tumor immune evasion through HLA downregulation or loss of heterozygosity remains a significant challenge for clinical efficacy (Pant et al., Nat Med 2024).

Other names

KRAS neoantigen-HLA complexKRAS mutant peptide-MHC class I complexKRAS G12D-HLA complexKRAS G12V-HLA complexKRAS pMHC

Targeting of the KRAS mutant peptide-HLA complex by engineered T-cell receptors (TCRs) or vaccine-induced T-cells, leading to selective cytotoxic T-lymphocyte (CTL) mediated recognition and lysis of tumor cells (Leidner et al., N Engl J Med 2022).