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Mol Cancer Res. 2019 Nov 8. doi: 10.1158/1541-7786.MCR-19-0141. [Epub ahead of print]

EZH2 Loss Drives Resistance to Carboplatin and Paclitaxel in Serous Ovarian Cancers Expressing ATM.

Author information

1
Department of Obstetrics and Gynecology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
2
Pharmaceutical Biotechnology, Eberhard Karls University of Tübingen, Tübingen, Germany.
3
NMI Technologietransfer GmbH, Reutlingen, Germany.
4
Department of Pathology, Ludwig Maximilian University of Munich, Munich, Germany.
5
Department of Pathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
6
Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.
7
Department of Gynecology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Germany.
8
Tumor Bank Ovarian Cancer Network (TOC), Berlin, Germany.
9
Department of Pathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Germany.
10
Department of Pathology and Neuropathology, Eberhard Karls University of Tübingen, Tübingen, Germany.
11
Department of Obstetrics and Gynecology, University Hospital of Tübingen, Tübingen, Germany.
12
Department of Obstetrics and Gynecology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany. hans.neubauer@med.uni-duesseldorf.de.

Abstract

Mechanisms of intrinsic resistance of serous ovarian cancers to standard treatment with carboplatin and paclitaxel are poorly understood. Seventeen primary serous ovarian cancers classified as responders or nonresponders to standard treatment were screened with DigiWest protein array analysis for 279 analytes. Histone methyl transferase EZH2, an interaction partner of ataxia telangiectasia mutated (ATM), was found as one of the most significantly represented proteins in responsive tumors. Survival analysis of 616 patients confirmed a better outcome in patients with high EZH2 expression, but a worse outcome in patients with low EZH2 and high-ATM-expressing tumors compared with patients with low EZH2 and low-ATM-expressing tumors. A proximity ligation assay further confirmed an association between ATM and EZH2 in tumors of patients with an increased disease-free survival. Knockdown of EZH2 resulted in treatment-resistant cells, but suppression of both EZH2 and ATM, or ATM alone, had no effect. DigiWest protein analysis of EZH2-knockdown cells revealed a decrease in proteins involved in mitotic processes and checkpoint regulation, suggesting that deregulated ATM may induce treatment resistance. IMPLICATIONS: Ovarian cancer is a malignancy with high mortality rates, with to date, no successful molecular characterization strategies. Our study uncovers in a comprehensive approach the involvement of checkpoint regulation via ATM and EZH2, potentially providing a new therapeutic perspective for further investigations.

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