Mutated Kirsten rat sarcoma virus oncogene homolog peptide–Major Histocompatibility Complex (mutated KRAS peptide–MHC) (mutated KRAS peptide–MHC)

Mutated KRAS peptide–Major Histocompatibility Complex (MHC) complexes represent a class of tumor-specific neoantigens formed when intracellular mutated KRAS proteins are degraded by the proteasome and their fragments are presented on the cell surface by MHC molecules. KRAS is one of the most frequently mutated oncogenes in human cancers, particularly in pancreatic, colorectal, and non-small cell lung cancers, where mutations like G12D, G12V, and G12C drive malignant transformation (Simanshu et al., 2017, Cell). These complexes are highly attractive therapeutic targets because they are absent in normal tissues, providing a wide therapeutic window for immunotherapies (Bear et al., 2020, Cancer Discovery). Current drug development efforts focus on T-cell receptor (TCR) engineered T-cell therapies, which utilize synthetic TCRs to recognize specific peptide-HLA combinations, and cancer vaccines like ELI-002 that prime the endogenous immune system (Leidner et al., 2022, NEJM). These therapies aim to bypass the "undruggable" nature of the intracellular KRAS protein by targeting the extracellular presentation of its mutant fragments. Despite their promise, targeting these complexes requires precise matching of the patient's HLA genotype and the specific KRAS mutation, and therapeutic efficacy can be hindered by tumor-mediated HLA downregulation (Wang et al., 2019, Science Immunology). Additionally, safety concerns include potential cross-reactivity with wild-type proteins and the risk of cytokine release syndrome.

Other names

KRAS neoantigen-MHC complexKRAS mutant peptide-HLA complexKRAS-HLA complexpHLA KRAS

Therapeutic agents, such as TCR-engineered T-cells or bispecific molecules, recognize the specific mutant KRAS peptide sequence in the context of a particular HLA allele, triggering an immune response that leads to the selective destruction of the mutant-expressing tumor cells.