在高级别卵巢癌细胞中,溴域抑制剂i-BET858触发了一种独特的转录反应,与增强的DNA损伤、细胞周期阻滞和细胞凋亡相关。

IF 5.7 2区 医学 Q1 Medicine Clinical Epigenetics Pub Date : 2023-04-15 DOI:10.1186/s13148-023-01477-x
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, Lewis W Francis
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引用次数: 1

摘要

背景:卵巢癌具有特殊的未满足的临床需求,在晚期疾病的妇女中观察到持续较低的5年生存率,需要继续努力开发新的治疗方案。BRD4在高级别浆液性卵巢癌(HGSC)的显著亚群中的扩增导致了BET抑制剂(BETi)作为有前途的抗肿瘤药物的发展,这些药物随后在I/II期临床试验中进行了评估。在这里,我们描述了i-BET858的分子效应和体外临床前活性,i-BET858是一种被证明具有体内BRD抑制活性的二价泛bet抑制剂。结果:i-BET858在HGSC临床样本的细胞系和原代细胞中均表现出比前代BETis更强的细胞毒活性。在分子水平上,i-BET858触发了两部分转录反应,包括一个通常与实体肿瘤中BET抑制相关的基因“核心”网络,以及一个独特的i-BET858基因标记。与i-BET151相比,i-BET858在机制上引起了DNA损伤、细胞周期阻滞和细胞凋亡。结论:总的来说,我们的离体和体外研究表明,i-BET858是进一步临床验证治疗HGSC的最佳候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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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.

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.

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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
期刊最新文献
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