1. Combined inhibition of EZH2 and ATM is synthetic lethal in BRCA1-deficient breast cancer.
- Author
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Ratz L, Brambillasca C, Bartke L, Huetzen MA, Goergens J, Leidecker O, Jachimowicz RD, van de Ven M, Proost N, Siteur B, de Korte-Grimmerink R, Bouwman P, Pulver EM, de Bruijn R, Isensee J, Hucho T, Pandey G, van Lohuizen M, Mallmann P, Reinhardt HC, Jonkers J, and Puppe J
- Subjects
- Animals, Cell Line, Tumor, Female, Humans, Mammary Neoplasms, Experimental drug therapy, Mammary Neoplasms, Experimental metabolism, Mammary Neoplasms, Experimental pathology, Mice, Synthetic Lethal Mutations, Antineoplastic Combined Chemotherapy Protocols pharmacology, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Ataxia Telangiectasia Mutated Proteins metabolism, BRCA1 Protein deficiency, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Breast Neoplasms pathology, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Enhancer of Zeste Homolog 2 Protein genetics, Enhancer of Zeste Homolog 2 Protein metabolism, Indoles pharmacology, Protein Kinase Inhibitors pharmacology, Pyridones pharmacology
- 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., (© 2022. The Author(s).)
- Published
- 2022
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