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

Quintela, Marcos, James, David W., Pociute, Agne, Powell, Lydia, Edwards, Kadie, Coombes, Zoe, Garcia, Jetzabel, Garton, Neil, Das, Nagindra, Lutchman-Singh, Kerryn, Margarit, Lavinia, Beynon, Amy L., Rioja, Inmaculada, Prinjha, Rab K., Harker, Nicola R., Gonzalez, Deyarina, Conlan, R. Steven and Francis, Lewis W. 2023. 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. Clinical Epigenetics 15 (1) , 63. 10.1186/s13148-023-01477-x

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	BioMed Central
ISSN:	1868-7083
Date of Acceptance:	29 March 2023
Last Modified:	19 Sep 2024 09:00
URI:	https://orca.cardiff.ac.uk/id/eprint/172011

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