التفاصيل البيبلوغرافية
| العنوان: |
Combined inhibition of EZH2 and ATM is synthetic lethal in BRCA1-deficient breast cancer. |
| المؤلفون: |
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 |
| المصدر: |
Breast Cancer Research; 6/17/2022, Vol. 24 Issue 1, p1-19, 19p |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
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