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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
,
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 ,
Lewis Francis ,
Amy Johnson
Clinical Epigenetics, Volume: 15, Issue: 1
Swansea University Authors:
Marcos Quintela Vazquez, David James, Agne Baseviciene, Lydia Powell , Steve Conlan , Lewis Francis , Amy Johnson
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DOI (Published version): 10.1186/s13148-023-01477-x
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...
| Published in: | Clinical Epigenetics |
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| ISSN: | 1868-7083 |
| Published: |
Springer Science and Business Media LLC
2023
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| Online Access: |
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| 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. |
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| 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 |