Epigenetic library screen reveals novel targets for uveal melanoma
Uveal melanoma (UM) is the most common primary ocular cancer in adults, which metastasizes mainly to the liver in around half of the cases. The limited potency of current treatment options for metastatic UM necessitates an urgent exploration of novel therapeutic approaches to improve patient prognosis. We conducted a large epigenetic compound library screen with the currently most well characterized, focused epigenetics library available, which consists of 932 potent, cell permeable, medically active, epigenetic-directed small molecule modulators. Our screening identified two new lead compounds, which so-far have been unappreciated for UM. Romidepsin, an HDAC inhibitor with specificity for class I HDACs, was the most efficient compound in-vitro, as well as the BET inhibitor Mivebresib, which showed minimal toxicity on normal cells. RNA sequencing and pathway analysis revealed an upregulation of PRC-associated gene targets induced by HDAC inhibition, while BET inhibition appears to act through retinoic acid related pathways. Mivebresib treatment in a metastatic uveal melanoma mouse model resulted in longer survival times and reduced metastasis to the spinal cord and brain. The results of our drug screen indicate a vulnerability for HDAC and BET inhibition for UM cells. The BET inhibitor Mivebresib may be a promising candidate for future synergistic and clinical trials. Overall design: To investigate the effects on transcription of treatment with epigenetic compounds of interest on uveal melanoma cells, we subjected human uveal melanoma cell line MP41 to 24 hours of high dose treatment with each drug. Bulk RNA sequencing followed by analysis through BioJupies was performed to determine differential gene expression in treated cells.