Synthetic lethality in CCNE1-amplified high grade serous ovarian cancer through combined inhibition of polo-like kinase 1 and microtubule dynamics

Sabrina Noack, Monika Raab, Yves Matthess, Mourad Sanhaji, Andrea Krämer, Balázs Gyorffy, Lars Kaderali, Ahmed El-Balat, Sven Becker, Klaus Strebhardt

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

The taxanes are effective microtubule-stabilizing chemotherapy drugs that inhibit mitosis, induce apoptosis, and produce regression in a fraction of cancers that arise at many sites including the ovary. Novel therapeutic targets that augment taxane effects are needed to improve clinical chemotherapy response in CCNE1-amplified high grade serous ovarian cancer (HGSOC) cells. In this study, we conducted an siRNA-based kinome screen to identify modulators of mitotic progression in CCNE1-amplified HGSOC cells that may influence clinical paclitaxel response. PLK1 is overexpressed in many types of cancer, which correlates with poor prognosis. Here, we identified a novel synthetic lethal interaction of the clinical PLK1 inhibitor BI6727 and the microtubuletargeting drug paclitaxel in HGSOC cell lines with CCNE1-amplification and elucidated the underlying molecular mechanisms of this synergism. BI6727 synergistically induces apoptosis together with paclitaxel in different cell lines including a patient-derived primary ovarian cancer culture. Moreover, the inhibition of PLK1 reduced the paclitaxelinduced neurotoxicity in a neurite outgrowth assay. Mechanistically, the combinatorial treatment with BI6727/paclitaxel triggers mitotic arrest, which initiates mitochondrial apoptosis by inactivation of anti-apoptotic BCL-2 family proteins, followed by significant loss of the mitochondrial membrane potential and activation of caspase-dependent effector pathways. This conclusion is supported by data showing that BI6727/ paclitaxel-co-treatment stabilizes FBW7, a component of SCF-type ubiquitin ligases that bind and regulate key modulators of cell division and growth including MCL-1 and Cyclin E. This identification of a novel synthetic lethality of PLK1 inhibitors and a microtubule-stabilizing drug has important implications for developing PLK1 inhibitorbased combination treatments in CCNE1-amplified HGSOC cells.

Original languageEnglish
Pages (from-to)25842-25859
Number of pages18
JournalOncotarget
Volume9
Issue number40
DOIs
Publication statusPublished - 2018

Keywords

  • Cell cycle
  • Ovarian cancer
  • Paclitaxel
  • Protein kinases
  • Sensitization

ASJC Scopus subject areas

  • Oncology

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    Noack, S., Raab, M., Matthess, Y., Sanhaji, M., Krämer, A., Gyorffy, B., Kaderali, L., El-Balat, A., Becker, S., & Strebhardt, K. (2018). Synthetic lethality in CCNE1-amplified high grade serous ovarian cancer through combined inhibition of polo-like kinase 1 and microtubule dynamics. Oncotarget, 9(40), 25842-25859. https://doi.org/10.18632/oncotarget.25386