Ratz, Leonie, Brambillasca, Chiara, Bartke, Leandra, Huetzen, Maxim A., Goergens, Jonas, Leidecker, Orsolya, Jachimowicz, Ron D., van de Ven, Marieke, Proost, Natalie, Siteur, Bjorn, de Korte-Grimmerink, Renske, Bouwman, Peter ORCID: 0000-0002-9252-5896, Pulver, Emilia M., de Bruijn, Roebi, Isensee, Joerg, Hucho, Tim ORCID: 0000-0002-4147-9308, Pandey, Gaurav, van Lohuizen, Maarten, Mallmann, Peter, Reinhardt, Hans Christian, Jonkers, Jos ORCID: 0000-0002-9264-9792 and Puppe, Julian (2022). Combined inhibition of EZH2 and ATM is synthetic lethal in BRCA1-deficient breast cancer. Breast Cancer Res., 24 (1). LONDON: BMC. ISSN 1465-542X

Full text not available from this repository.

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ratz, LeonieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brambillasca, ChiaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartke, LeandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huetzen, Maxim A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goergens, JonasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leidecker, OrsolyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jachimowicz, Ron D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van de Ven, MariekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Proost, NatalieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Siteur, BjornUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Korte-Grimmerink, RenskeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bouwman, PeterUNSPECIFIEDorcid.org/0000-0002-9252-5896UNSPECIFIED
Pulver, Emilia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Bruijn, RoebiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isensee, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hucho, TimUNSPECIFIEDorcid.org/0000-0002-4147-9308UNSPECIFIED
Pandey, GauravUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Lohuizen, MaartenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mallmann, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinhardt, Hans ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jonkers, JosUNSPECIFIEDorcid.org/0000-0002-9264-9792UNSPECIFIED
Puppe, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-688334
DOI: 10.1186/s13058-022-01534-y
Journal or Publication Title: Breast Cancer Res.
Volume: 24
Number: 1
Date: 2022
Publisher: BMC
Place of Publication: LONDON
ISSN: 1465-542X
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PATHOLOGICAL COMPLETE RESPONSE; TUMOR-SUPPRESSOR; MAMMARY-TUMORS; BRCA1; POLYCOMB; METHYLATION; COMPLEXES; MODIFIERS; LYMPHOMA; REPAIRMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68833

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item