Introduction The FGF/FGFR signaling pathway is known to have a critical role in physiological and pathological processes in human cancers. We analyzed the anti-tumor effect of AZD4547, an inhibitor targeting the FGF/FGFR pathway in epithelial ovarian cancer (EOC).

Methods We treated EOC cells with AZD4547 to evaluate its effects on cell viability and migration. In vivo experiments in orthotopic xenografts using EOC cells and a patient derived xenograft (PDX) model were also performed. Combination effect of AZD4547 and either SU11274, a c-Met-specific inhibitor, or FGF19-specific siRNA was evaluated by MTT assay.

Results AZD4547 significantly decreased cell survival and migration in EOC cells except for A2780-CP20 and SKOV3-TR cells. AZD4547 significantly decreased tumor weight in xenograft models of EOC cells and in a PDX model established with platinum-sensitive tumors but not in A2780-CP20 and SKOV3-TR. Expression of c-Met in SKOV3-TR cells was higher than other cells and combination of SU11274 and AZD4547 increased cell death. Although FGFR1–3 proteins were relatively highly expressed in EOC cells used in this study, FGFR4 was strongly expressed only in A2780 and A2780-CP20. In addition, FGF19 expression, a ligand for FGFR4, was exclusively high in A2780-CP20 cells. Combining AZD4547 with FGF19 siRNA or with a selective FGFR4 inhibitor led to significantly reduced cell proliferation in A2780-CP20.

Conclusion/Implications We suggest that expression level of c-Met or FGF19 can be a predictive biomarker for AZD4547 treatment and that combination therapy of drugs targeting c-Met or FGF19 with AZD4547 can be an effective therapeutic strategy for treating resistant EOCs.