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dc.contributor.author Noack S
dc.contributor.author Raab M
dc.contributor.author Matthess Y
dc.contributor.author Sanhaji M
dc.contributor.author Kramer A
dc.contributor.author Győrffy, Balázs
dc.contributor.author Kaderali L
dc.contributor.author El-Balat A
dc.contributor.author Becker S
dc.contributor.author Strebhardt K
dc.date.accessioned 2018-06-28T06:55:26Z
dc.date.available 2018-06-28T06:55:26Z
dc.date.issued 2018
dc.identifier.citation pagination=25842-25859; journalVolume=9; journalIssueNumber=40; journalTitle=ONCOTARGET;
dc.identifier.uri http://repo.lib.semmelweis.hu//handle/123456789/5667
dc.identifier.uri doi:10.18632/oncotarget.25386
dc.description.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 microtubule-targeting 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 paclitaxel-induced 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 inhibitor-based combination treatments in CCNE1-amplified HGSOC cells.
dc.relation.ispartof urn:issn:1949-2553
dc.title Synthetic lethality in CCNE1-amplified high grade serous ovarian cancer through combined inhibition of Polo-like kinase 1 and microtubule dynamics
dc.type Journal Article
dc.date.updated 2018-06-22T11:24:17Z
dc.language.rfc3066 en
dc.identifier.mtmt 3388807
dc.identifier.pubmed 29899826
dc.contributor.department SE/AOK/K/II. Sz. Gyermekgyógyászati Klinika
dc.contributor.institution Semmelweis Egyetem


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