BRCA1-Associated Protein 1 and Enhancer of Zeste Homolog 2: Pathway Interaction and Therapeutic Intervention in Breast Cancer, Mesothelioma, and Lymphoma.

Abstract

BRCA1-associated protein 1 (BAP1) and Enhancer of zeste homolog 2 (EZH2) proteins are associated with the Polycomb repressive complex (PRC), and both have key roles in cell cycle and DNA repair pathways, so variants in <i>BAP1</i> and/or <i>EZH2</i> could lead to tumorigenesis. Somatic and germline variants in these genes have been associated with uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma (<i>BAP1</i> loss-of-function variants), and lymphoma, leukemia, and triple-negative breast cancer (<i>EZH2</i> gain-of-function variants). Loss of <i>BAP1</i> function in the murine model has been shown to lead to an overexpression of <i>EZH2</i> mRNA. Tazemetostat is a selective EZH2 inhibitor currently approved for the treatment of follicular lymphoma in the third line. The effects of tazemetostat have been studied in clinical trials for patients with <i>BAP1</i> and <i>EZH2</i> pathogenic variants with malignant mesothelioma and it has shown significant results when used in combination with poly (ADP-ribose) polymerase inhibitors on breast cancer cell lines. The interaction of BAP1 and EZH2 and the efficacy of tazemetostat show great potential for the future of cancer treatment for patients harboring variants in those genes due to the more aggressive nature of those tumors and the lack of targeted treatments.