CEP-1347 Enhances the Sensitivity of Ovarian Clear Cell Carcinoma Cells to Navitoclax by Downregulating MCL1

Ovarian clear cell carcinoma (OCCC) is a rare, but highly malignant subtype of epithelial ovarian cancer that is characterized by inherent chemoresistance and limited treatment options, underscoring the need for effective and novel therapeutic approaches. We previously reported the cytotoxic effects of the combination of CEP-1347, a kinase inhibitor that induces cytostatic effects by activating the p53-p21 pathway, and navitoclax in OCCC cells; however, the mechanisms underlying this sensitization remain unclear. We herein demonstrated that the CEP-1347/navitoclax combination induced cell death in OCCC cells with different TP53 gene statuses. Instead, a Western blot analysis of anti-apoptotic factors suggested that CEP-1347 sensitized OCCC cells to navitoclax by inhibiting MCL1 expression. In support of this, the downregulation of MCL1 sensitized OCCC cells to navitoclax, whereas MCL1 overexpression attenuated CEP-1347/navitoclax-induced cell death. Unlike S63845, an MCL1-targeting BH3 mimetic that sensitized normal cells as well as OCCC cells, CEP-1347 preferentially sensitized OCCC cells to navitoclax without affecting normal cells. These results suggest the potential of CEP-1347-based combination treatment, which preferentially sensitizes OCCC cells to navitoclax by downregulating MCL1, as a safer alternative to MCL1-targeted BH3 mimetics, and provide support for further investigations on this combination as a therapeutic strategy for OCCC.