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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

Marcos Quintela Vazquez, David James, Agne Pociute, Lydia Powell Orcid Logo, 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, Steve Conlan Orcid Logo, Lewis Francis Orcid Logo, Amy Johnson

Clinical Epigenetics, Volume: 15, Issue: 1

Swansea University Authors: Marcos Quintela Vazquez, David James, Agne Pociute, Lydia Powell Orcid Logo, Steve Conlan Orcid Logo, Lewis Francis Orcid Logo, Amy Johnson

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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 car...

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Published in: Clinical Epigenetics
ISSN: 1868-7083
Published: Springer Science and Business Media LLC 2023
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa64098
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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.
Keywords: Ovarian cancer, BETi, Advanced therapeutics, Drug development, i-BET858
College: Faculty of Medicine, Health and Life Sciences
Funders: The research conducted herein was funded by SMARTExpertise programmes CEAT and RISE via the Welsh Government and the European Regional Development Fund (2017/COL/004; 2017/COL/001).
Issue: 1