CDK6 protects epithelial ovarian cancer from platinum-induced death via FOXO3 regulation

Alessandra Dall'Acqua, Maura Sonego, Ilenia Pellizzari, Ilenia Pellarin, Vincenzo Canzonieri, Sara D'Andrea, Sara Benevol, Roberto Sorio, Giorgio Giorda, Daniela Califano, Marina Bagnoli, Loredana Militello, Delia Mezzanzanica, Gennaro Chiappetta, Joshua Armenia, Barbara Belletti, Monica Schiappacassi, Gustavo Baldassarre

Research output: Contribution to journalArticle

Abstract

Epithelial ovarian cancer (EOC) is an infrequent but highly lethal disease, almost invariably treated with platinum-based therapies. Improving the response to platinum represents a great challenge, since it could significantly impact on patient survival. Here, we report that silencing or pharmacological inhibition of CDK6 increases EOC cell sensitivity to platinum. We observed that, upon platinum treatment, CDK6 phosphorylated and stabilized the transcription factor FOXO3, eventually inducing ATR transcription. Blockage of this pathway resulted in EOC cell death, due to altered DNA damage response accompanied by increased apoptosis. These observations were recapitulated in EOC cell lines in vitro, in xenografts in vivo, and in primary tumor cells derived from platinum-treated patients. Consistently, high CDK6 and FOXO3 expression levels in primary EOC predict poor patient survival. Our data suggest that CDK6 represents an actionable target that can be exploited to improve platinum efficacy in EOC patients. As CDK4/6 inhibitors are successfully used in cancer patients, our findings can be immediately transferred to the clinic to improve the outcome of EOC patients.

Original languageEnglish
Pages (from-to)1415-1433
Number of pages19
JournalEMBO Molecular Medicine
Volume9
Issue number10
DOIs
Publication statusPublished - Oct 2017

Keywords

  • Journal Article

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