Kirsten rat sarcoma virus oncogene homolog mutated antigens (KRAS neoantigens)

KRAS-mutated tumor cell antigens are neoantigens derived from somatic mutations in the Kirsten rat sarcoma virus oncogene homolog (KRAS) gene, a critical component of the RAS/MAPK signaling pathway (UniProt P01116). These mutations, primarily occurring at codons 12, 13, or 61 (e.g., G12C, G12D, G12V), result in a constitutively active oncoprotein that drives uncontrolled cell growth and survival in several major cancers, including pancreatic, colorectal, and non-small cell lung cancer (NIH/NCI). Within tumor cells, these mutant proteins are processed into peptide fragments and presented on the cell surface by Human Leukocyte Antigen (HLA) molecules. These peptide-MHC complexes are recognized as "non-self" by the immune system, making them highly specific targets for precision immunotherapies such as cancer vaccines (e.g., ELI-002) and adoptive T-cell therapies (TCR-T) (Nature Medicine, 2024). While small-molecule inhibitors like sotorasib and adagrasib target the mutant protein's enzymatic activity, the resulting drug-protein complexes can also be presented as unique "haptenated" antigens, potentially synergizing with immunotherapy to overcome resistance and improve patient outcomes (Cancer Cell, 2022).

Other names

KRAS neoantigensMutant KRAS antigensmKRAS epitopesKRAS-derived neoepitopesKRAS-mutant tumor antigens

Mechanisms include the covalent inhibition of the mutant KRAS protein in its inactive GDP-bound state, the induction of mutation-specific CD4+ and CD8+ T-cell responses via peptide or mRNA vaccines, and the direct targeting of peptide-MHC complexes by engineered T-cell receptors (TCR-T) or bispecific antibodies.