1. Bromodomain inhibitor i-BET858 triggers a unique transcriptional response coupled to enhanced DNA damage, cell cycle arrest and apoptosis in high-grade ovarian carcinoma cells
- Author
-
Marcos Quintela, David W. James, Agne Pociute, Lydia Powell, Kadie Edwards, Zoe Coombes, Jetzabel Garcia, Neil Garton, Nagindra Das, Kerryn Lutchman-Singh, Lavinia Margarit, Amy L. Beynon, Inmaculada Rioja, Rab K. Prinjha, Nicola R. Harker, Deyarina Gonzalez, R. Steven Conlan, and Lewis W. Francis
- Subjects
Ovarian cancer ,BETi ,Advanced therapeutics ,Drug development ,i-BET858 ,Medicine ,Genetics ,QH426-470 - Abstract
Abstract Background Ovarian cancer has a specific unmet clinical need, with a persistently poor 5-year survival rate observed in women with advanced stage disease warranting continued efforts to develop new treatment options. The amplification of BRD4 in a significant subset of high-grade serous ovarian carcinomas (HGSC) has led to the development of BET inhibitors (BETi) as promising antitumour agents that have subsequently been evaluated in phase I/II clinical trials. Here, we describe the molecular effects and ex vivo preclinical activities of i-BET858, a bivalent pan-BET inhibitor with proven in vivo BRD inhibitory activity. Results i-BET858 demonstrates enhanced cytotoxic activity compared with earlier generation BETis both in cell lines and primary cells derived from clinical samples of HGSC. At molecular level, i-BET858 triggered a bipartite transcriptional response, comprised of a ‘core’ network of genes commonly associated with BET inhibition in solid tumours, together with a unique i-BET858 gene signature. Mechanistically, i-BET858 elicited enhanced DNA damage, cell cycle arrest and apoptotic cell death compared to its predecessor i-BET151. Conclusions Overall, our ex vivo and in vitro studies indicate that i-BET858 represents an optimal candidate to pursue further clinical validation for the treatment of HGSC.
- Published
- 2023
- Full Text
- View/download PDF