EZH2 inhibition sensitizes BRCA1-deficient breast cancer cells to synthetic lethal therapy with ATM inhibitors

Background The majority of BRCA1-mutant breast cancers are characterized by a triple-negative phenotype (TNBC) and a basal-like molecular subtype, associated with an 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 cells lines derived from BRCA1-deficient and BRCA1-proficient mouse mammary tumors.

Results We identified 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 combination treatment of 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 suggest considering the synergistic interaction between EZH2 and ATM as novel molecular combination for the treatment of BRCA1-mutant breast cancer.

Interessenkonflikt

H.C.R. received consulting and lecture fees from Abbvie, AstraZeneca, Vertex and Merck. H.C.R. received research funding from Gilead Pharmaceuticals. H.C.R. is a co-founder of CDL Therapeutics GmbH.

Publication History

Article published online:
01 June 2021