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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
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URI: https://cronfa.swan.ac.uk/Record/cronfa64098
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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. 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spelling v2 64098 2023-08-22 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 29d006fa16d293ca29762fce9c356f8e Marcos Quintela Vazquez Marcos Quintela Vazquez true false 31b39419835be9525450cf1420e63996 David James David James true false 84c6725e2bf8941faae8ed66821732fd Agne Pociute Agne Pociute true false 0e7e702952672bcbfdfd4974199202fb 0000-0002-8641-0160 Lydia Powell Lydia Powell true false 0bb6bd247e32fb4249de62c0013b51cb 0000-0002-2562-3461 Steve Conlan Steve Conlan true false 10f61f9c1248951c1a33f6a89498f37d 0000-0002-7803-7714 Lewis Francis Lewis Francis true false cd71e22a01d9a5d7e46cd8ef0fc28da1 Amy Johnson Amy Johnson true false 2023-08-22 BMS 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. Journal Article Clinical Epigenetics 15 1 Springer Science and Business Media LLC 1868-7083 Ovarian cancer, BETi, Advanced therapeutics, Drug development, i-BET858 15 4 2023 2023-04-15 10.1186/s13148-023-01477-x http://dx.doi.org/10.1186/s13148-023-01477-x COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University SU Library paid the OA fee (TA Institutional Deal) 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). 2024-03-12T11:40:40.1322426 2023-08-22T10:33:50.0059403 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Marcos Quintela Vazquez 1 David James 2 Agne Pociute 3 Lydia Powell 0000-0002-8641-0160 4 Kadie Edwards 5 Zoe Coombes 6 Jetzabel Garcia 7 Neil Garton 8 Nagindra Das 9 Kerryn Lutchman-Singh 10 Lavinia Margarit 11 Amy L. Beynon 12 Inmaculada Rioja 13 Rab K. Prinjha 14 Nicola R. Harker 15 Deyarina Gonzalez 16 Steve Conlan 0000-0002-2562-3461 17 Lewis Francis 0000-0002-7803-7714 18 Amy Johnson 19 64098__28687__e4a76e595e6e4fd8a66d0f7671c9b56a.pdf 64098.VOR.pdf 2023-10-03T13:17:33.3313571 Output 8343194 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. true eng http://creativecommons.org/licenses/by/4.0/
title 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
spellingShingle 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
Steve Conlan
Lewis Francis
Amy Johnson
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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_id_str_mv 29d006fa16d293ca29762fce9c356f8e
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author_id_fullname_str_mv 29d006fa16d293ca29762fce9c356f8e_***_Marcos Quintela Vazquez
31b39419835be9525450cf1420e63996_***_David James
84c6725e2bf8941faae8ed66821732fd_***_Agne Pociute
0e7e702952672bcbfdfd4974199202fb_***_Lydia Powell
0bb6bd247e32fb4249de62c0013b51cb_***_Steve Conlan
10f61f9c1248951c1a33f6a89498f37d_***_Lewis Francis
cd71e22a01d9a5d7e46cd8ef0fc28da1_***_Amy Johnson
author Marcos Quintela Vazquez
David James
Agne Pociute
Lydia Powell
Steve Conlan
Lewis Francis
Amy Johnson
author2 Marcos Quintela Vazquez
David 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
Steve Conlan
Lewis Francis
Amy Johnson
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container_title Clinical Epigenetics
container_volume 15
container_issue 1
publishDate 2023
institution Swansea University
issn 1868-7083
doi_str_mv 10.1186/s13148-023-01477-x
publisher Springer Science and Business Media LLC
college_str Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title Faculty of Medicine, Health and Life Sciences
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hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
url http://dx.doi.org/10.1186/s13148-023-01477-x
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description 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.
published_date 2023-04-15T11:40:37Z
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