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Ratz, Leonie; 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

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

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  • Medientyp: E-Artikel
  • Titel: Combined inhibition of EZH2 and ATM is synthetic lethal in BRCA1-deficient breast cancer
  • Beteiligte: Ratz, Leonie; 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
  • Erschienen: Springer Science and Business Media LLC, 2022
  • Erschienen in: Breast Cancer Research
  • Sprache: Englisch
  • DOI: 10.1186/s13058-022-01534-y
  • ISSN: 1465-542X
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>The majority of <jats:italic>BRCA1</jats:italic>-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.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>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. </jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>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. </jats:p> </jats:sec><jats:sec> <jats:title>Conclusion</jats:title> <jats:p>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 <jats:italic>BRCA1</jats:italic>-mutant breast cancer.</jats:p> </jats:sec>
  • Zugangsstatus: Freier Zugang