Estrogen receptor 1-Parkin RBR E3 ubiquitin protein ligase fusion protein neoantigens (ESR1-PRKN)

ESR1-PRKN fusion protein neoantigens are novel immunogenic peptides derived from a chimeric protein resulting from the genomic rearrangement between the Estrogen Receptor 1 (ESR1) and Parkin RBR E3 Ubiquitin Protein Ligase (PRKN) genes. This specific fusion, frequently involving exons 1-8 of ESR1 and exons 4-12 of PRKN, is a recurrent driver in estrogen receptor-positive (ER+) breast cancer, particularly in metastatic cases that have developed resistance to standard endocrine therapies and CDK4/6 inhibitors. Because the fusion creates a unique amino acid sequence at the junction point that is absent in normal tissues, it serves as a highly specific source of neoantigens for the immune system. Research has demonstrated that these neoantigens can elicit robust, HLA-restricted cytotoxic T-cell responses, making them ideal targets for personalized immunotherapy. Current therapeutic strategies focus on the development of personalized mRNA and peptide-based cancer vaccines designed to prime the immune system to recognize and eliminate tumor cells expressing the ESR1-PRKN fusion. Beyond its role as an immunological target, the fusion protein often retains the DNA-binding domain of ESR1 while losing the ligand-binding domain, leading to constitutive, estrogen-independent transcriptional activity that drives tumor progression and drug resistance. Therefore, targeting the resulting neoantigens offers a precision medicine approach to overcome secondary resistance in advanced breast cancer.

Other names

ESR1-PRKN fusion neoantigensESR1-PARK2 fusionER-Parkin fusion proteinEstrogen receptor alpha-Parkin fusionESR1(e1-8)-PRKN(e4-12) neoantigens

Induction of tumor-specific CD8+ and CD4+ T-cell responses against unique junctional neopeptides presented on Major Histocompatibility Complex (MHC) molecules, such as HLA-A*01:01, to promote immune-mediated destruction of cancer cells harboring the fusion protein.