Blocking Mitotic Exit of Ovarian Cancer Cells by Pharmaceutical Inhibition of the Anaphase-Promoting Complex Reduces Chromosomal Instability

Paclitaxel is a frontline drug for the treatment of epithelial ovarian Cancer (EOC). However, following paclitaxel-platinum based chemotherapy, tumor recurrence occurs in most ovarian Cancer patients. Chromosomal instability (CIN) is a hallmark of Cancer and represents genetic variation fueling tumor adaptation to cytotoxic effects of Anticancer drugs. In this study, our Kaplan-Meier analysis including 263 ovarian Cancer patients (stages I/II) revealed that high Polo-like kinase (PLK) 1 expression correlates with bad prognosis. To evaluate the role of PLK1 as potential Cancer target within a combinatorial trial, we induced strong mitotic arrest in ovarian Cancer cell lines by synergistically co-targeting microtubules (paclitaxel) and PLK1 (BI6727) followed by pharmaceutical inhibition of the Anaphase-Promoting Complex (APC/C) using proTAME. In short- and long-term experiments, this triple treatment strongly activated Apoptosis in cell lines and primary ovarian cells derived from Cancer patients. Mechanistically, BI6727/paclitaxel/proTAME stabilize Cyclin B1 and trigger mitotic arrest, which initiates mitochondrial Apoptosis by inactivation of antiapoptotic Bcl-2 Family proteins, followed by activation of caspase-dependent effector pathways. This triple treatment prevented endoreduplication and reduced CIN, two mechanisms that are associated with aggressive tumors and the acquisition of drug resistance. This "two-punch strategy" (strong mitotic arrest followed by blocking mitotic exit) has important implications for developing paclitaxel-based combinatorial treatments in ovarian Cancer.