DNAJB1-PRKACA fusion protein neoepitope (DNAJB1-PRKACA)

The DNAJB1-PRKACA fusion protein neoepitope is the hallmark molecular driver of fibrolamellar hepatocellular carcinoma (FLC), a rare liver malignancy (Honeyman et al., Science, 2014). This target is generated by a somatic 400-kilobase deletion on chromosome 19, resulting in the fusion of the DNAJB1 gene and the PRKACA gene (National Cancer Institute). The fusion protein maintains constitutive PKA kinase activity, which disrupts normal cellular signaling and promotes tumorigenesis (PubMed, PMID: 24578576). Crucially, the junction where the two proteins meet creates a novel peptide sequence, or neoepitope, that is entirely tumor-specific (Diller et al., Nature Communications, 2020). This unique sequence allows for the development of highly targeted immunotherapies, such as peptide-based vaccines (e.g., FLC-VAC) and T-cell receptor (TCR) engineered T-cells, which aim to direct the immune system to destroy cancer cells while sparing healthy tissue (ClinicalTrials.gov, NCT04248569). Current clinical research is focused on identifying the specific HLA alleles, such as HLA-A*02:01, that can effectively present these neoepitopes to the immune system to maximize therapeutic efficacy (Eureka Therapeutics).

Other names

DNAJB1-PRKACA fusionFibrolamellar hepatocellular carcinoma fusion proteinDNAJB1-PRKACA junctional neoantigenFLC fusion protein

Induction of tumor-specific T-cell responses against the unique peptide sequence formed at the fusion junction of DNAJB1 and PRKACA.