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

Breast Cancer Res. 2022 Jun 17;24(1):41. doi: 10.1186/s13058-022-01534-y.


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.

Keywords: BRCA1 mutation; Breast cancer; EZH2; Synthetic lethality.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • 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
  • Cell Line, Tumor
  • Enhancer of Zeste Homolog 2 Protein* / antagonists & inhibitors
  • Enhancer of Zeste Homolog 2 Protein* / genetics
  • Enhancer of Zeste Homolog 2 Protein* / metabolism
  • Female
  • Humans
  • Indoles* / pharmacology
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice
  • Protein Kinase Inhibitors* / pharmacology
  • Pyridones* / pharmacology
  • Synthetic Lethal Mutations


  • BRCA1 Protein
  • BRCA1 protein, human
  • GSK-2816126
  • Indoles
  • Protein Kinase Inhibitors
  • Pyridones
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins