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Ratz, L.; Brambillasca, C.S.; Bartke, L.; Huetzen, M.A.; Goergens, J.; Leidecker, O.; ... ; Puppe, J. (2022)

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

Article / Letter to editor
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...Show moreBackground: 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.Show less
All authors
Ratz, L.; Brambillasca, C.S.; Bartke, L.; Huetzen, M.A.; Goergens, J.; Leidecker, O.; Jachimowicz, R.D.; Ven, M. van de; Proost, N.; Siteur, B.; Korte-Grimmerink, R. de; Bouwman, R.J.P.; Pulver, E.M.; Bruijn, R. de; Isensee, J.; Hucho, T.; Pandey, G.; Lohuizen, M.; Mallmann, P.; Reinhardt, H.C.; Jonkers, J.M.M.; Puppe, J.
Date
2022-06-17
Journal
Breast Cancer Research
Volume
24
Issue
1
DOI
doi:10.1186/s13058-022-01534-y