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

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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish
Article number41
JournalBreast Cancer Research
Volume24
Issue number1
DOIs
StatePublished - Dec 2022
Externally publishedYes

Keywords

  • BRCA1 mutation
  • Breast cancer
  • EZH2
  • Synthetic lethality

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