FGFR4 inhibition augments paclitaxel-induced cell death in ovarian cancer
Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, which has a high mortality rate due to frequent tumor recurrence. The development of drug resistance against the first-line chemotherapeutic agent, such as paclitaxel/Taxol®, represents a critical reason. The mechanisms of paclitaxel resistance remain largely unknown, and druggable drivers which can be targeted to prevent or revert paclitaxel resistance also need to be identified. Phos-tag-based screens in cells treated with paclitaxel were used to identify key regulators involved in paclitaxel resistance, such as fibroblast growth factor receptor 4 (FGFR4). The functional role of FGFR4 in regulating paclitaxel resistance was further identified using apoptosis assays, which included the identification of apoptotic marker levels and activities. The involvement of FGFR4 downstream signaling pathways involved in paclitaxel resistance were identified through western blotting and quantitative PCR. Their roles in regulating paclitaxel resistance were also validated using apoptosis assays. Immunofluorescent staining was performed to identify the synergy of paclitaxel and FGFR4 inhibition. Functional in vitro and in vivo studies demonstrate that FGFR4 depletion suppresses ovarian cancer cell proliferation, migration, and tumor growth. Importantly, FGFR4 silencing or specific inhibition can sensitize ovarian cancer cells to paclitaxel, whereas FGFR4 overexpression confers paclitaxel resistance. Mechanistically, FGFR4 regulates paclitaxel sensitivity in EOC cells through modulating the expression of the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-xL) via MEK-ERK-RSK signaling pathway. The inhibition of Bcl-xL or MEK-ERK-RSK signaling can also enhance paclitaxel-stimulated cytotoxicity. These findings indicate that targeting FGFR4 can be a promising novel strategy to overcome paclitaxel resistance and improve the outcomes of EOC patients.