br CIN is of particular interest because it is
. CIN is of particular interest because it is associated with aggressive tumors, the acquisition of drug resistance, and poor patient prognosis [59–62]. Multiple investigations described genome instability in ovarian cancer [63–65], which is characterized by gene copy number variations, rearranged genomes, structural variants, and single nucleo-tide variants. The treatment with paclitaxel and BI6727 increased chromosome numbers in ovarian cancer A 769662 significantly (Figure 5, Supplementary Figure S6). This result correlates with our previous observations showing that BI6727 induces slippage associated with mis-segregation of chromosomes . Only the triple treatment induced a high percentage of cells blocked in mitosis, thereby preventing an increase in chromosome numbers and preventing endoreduplication (Figures 4 and 5, Supplementary Figure S6). Endoreplication can contribute to genome instability . Recent work revealed that cancer cells use endoreplication as a path to drug resistance: Several cancer cell lines treated with growth-suppressing drugs enter endoreplication cycles [68,69]. Severe reduction of this process in triple-treated cells could reduce the oncogenic potential and chemoresistance in ovarian cancer cells. Together, by using the APC/C inhibitor proTAME for the treatment of mitotically arrested cells, we could present a tumor cells-suppressing strategy that is characterized by slippage inhibition and significant downregulation of chromosomal instability resulting in minimized long-term growth of ovarian cells.
Here, for the first time, our Kaplan-Meier analysis demonstrated the prognostic role of PLK1 expression in a cohort of 263 early-stage (I/II) ovarian cancer patients. We considered PLK1 as an ovarian cancer target and applied a combinatorial strategy using paclitaxel and a small molecule inhibitor of PLK1 to induce a strong mitotic arrest in ovarian cancer cells followed by an inhibition of the anaphase-promoting complex. By preventing the mitotic exit of ovarian cancer cells, this “two-punch strategy” reduces endoreduplication and strongly increases apoptosis. We revealed that this drug combination reduces mitotic slippage of paclitaxel-treated cells and reduces chromosomal instability, which is often associated with aggressive tumors and the acquisition of drug resistance. Thus, the “two punch strategy” might open novel avenues for the development of paclitaxel-based therapies of ovarian cancer patients.
This work was supported by grants from the Messer Stiftung (Germany), Research Support Foundation (Switzerland), Deutsche Krebshilfe (Germany), BANNS Stiftung (Germany), and DKTK (Germany).
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