Dual inhibition of EZH2 and ATM displays synergistic cytotoxicity in BRCA1-deficient breast cancers

Introduction Recently, we could show that EZH2 is significantly higher expressed in BRCA1-associated breast tumors and blocking EZH2 enzymatic activity might be a valid strategy for the treatment of BRCA1-mutant tumors. In this study, we investigated the effect of EZH2 inhibition in combination with DNA repair modulators to identify novel synthetic lethal interactions for the treatment of breast tumors with a BRCA1-deficiency.

Methods To determine whether EZH2 inhibition alone or in combination enhances sensitivity to Brca1-deficient tumors, we made use of cell lines that were derived from our Brca1-deficient and Brca1-proficient mouse model. Here, we analyzed gene expression data from tumor material and performed a large-scale cell line-based screen with the EZH2 inhibitor GSK126 and different pharmacological modulators of DNA repair and DNA damage response in a panel of breast cancer cell lines.

Results We could show that the ATM-CHK2 axis is significantly upregulated in Brca1-deficient breast tumors. Moreover, we identified a novel synergistic interaction between EZH2 and ATM inhibitors in Brca1-deficient tumor cells. Combined inhibition of EZH2 and ATM robustly induced apoptosis, particularly in Brca1-deficient cancer cells. Mechanistically, we found that combined inhibition of EZH2 and ATM led to the accumulation of yH2AX foci indicating increased genotoxic damage. These findings were supported by in vivo experiments, which revealed that simultaneous inhibition of EZH2 and ATM significantly reduced tumor volume in Brca1-deficient breast tumors.

Conclusion Here, we identified a synthetic lethal interaction between EZH2 and ATM paving the way for combined inhibition of EZH2 and ATM in BRCA1-mutant breast cancers.

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Publication History

Article published online:
07 October 2020