EZH2 loss drives resistance to carboplatin and paclitaxel in serous ovarian cancers expressing ATM

Johanna Naskou, Yvonne Beiter, Ruan van Rensburg, Ellen Honisch, Martina Rudelius, Martin Schlensog, Julia Gottstein, Larissa Walter, Elena I Braicu, Jalid Sehouli, Silvia Darb-Esfahani, Annette Staebler, Andreas D Hartkopf, Sara Brucker, Diethelm Wallwiener, Ines Beyer, Dieter Niederacher, Tanja Fehm, Markus F Templin, Hans Neubauer
Molecular Cancer Research: MCR 2019 November 8
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 non-responders to standard treatment were screened with DigiWest protein array analysis for 279 analytes. Histone methyl transferase EZH2, an interaction partner of 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 to 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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