Combined inhibition of EZH2 and ATM is synthetic lethal in BRCA1-deficient breast cancer

Author:

Ratz LeonieORCID,Brambillasca Chiara,Bartke Leandra,Huetzen Maxim A.,Goergens Jonas,Leidecker Orsolya,Jachimowicz Ron D.,van de Ven Marieke,Proost Natalie,Siteur Bjørn,de Korte-Grimmerink Renske,Bouwman Peter,Pulver Emilia M.,de Bruijn Roebi,Isensee Jörg,Hucho Tim,Pandey Gaurav,van Lohuizen Maarten,Mallmann Peter,Reinhardt Hans Christian,Jonkers Jos,Puppe Julian

Abstract

Abstract Background The majority of BRCA1-mutant breast cancers are characterized by a triple-negative phenotype and a basal-like molecular subtype, associated with aggressive clinical behavior. Current treatment options are limited, highlighting the need for the development of novel targeted therapies for this tumor subtype. Methods Our group previously showed that EZH2 is functionally relevant in BRCA1-deficient breast tumors and blocking EZH2 enzymatic activity could be a potent treatment strategy. To validate the role of EZH2 as a therapeutic target and to identify new synergistic drug combinations, we performed a high-throughput drug combination screen in various cell lines derived from BRCA1-deficient and -proficient mouse mammary tumors. Results We identified the combined inhibition of EZH2 and the proximal DNA damage response kinase ATM as a novel synthetic lethality-based therapy for the treatment of BRCA1-deficient breast tumors. We show that the combined treatment with the EZH2 inhibitor GSK126 and the ATM inhibitor AZD1390 led to reduced colony formation, increased genotoxic stress, and apoptosis-mediated cell death in BRCA1-deficient mammary tumor cells in vitro. These findings were corroborated by in vivo experiments showing that simultaneous inhibition of EZH2 and ATM significantly increased anti-tumor activity in mice bearing BRCA1-deficient mammary tumors. Conclusion Taken together, we identified a synthetic lethal interaction between EZH2 and ATM and propose this synergistic interaction as a novel molecular combination for the treatment of BRCA1-mutant breast cancer.

Funder

German-Israeli Foundation for Scientific Research and Development

Deutsche Forschungsgemeinschaft

José Carreras Leukämie-Stiftung

Else Kröner-Fresenius-Stiftung

Deutsche Krebshilfe

Bundesministerium für Bildung und Forschung

Universität zu Köln

KWF Kankerbestrijding

Lundbeckfonden

Nederlandse Organisatie voor Wetenschappelijk Onderzoek

Universitätsklinikum Köln

Publisher

Springer Science and Business Media LLC

Cited by 8 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3