Abstract 1229: Fibroblast growth factor signaling in ovarian cancer

Abstract

Abstract Epithelial ovarian cancer (OC) is a rapidly progressive, highly lethal disease. It is the fifth leading cause of cancer-related death among women. Over the last decades, there has been only modest improvement in the treatment of OC. Nevertheless, recent clinical trials with inhibitors of transmembrane receptor tyrosine kinases such as fibroblast growth factor (FGF) receptors (FGFRs) yielded some promising results in OC. FGFRs are involved in malignant transformation, angiogenesis and chemoresistance. Inhibition of FGFR-dependent signaling can overcome resistance to standard therapies. Thus, FGFRs represent potential targets for cancer therapy. Unfortunately, however, the biological and therapeutic relevance of the FGF-FGFR system has not been elucidated yet in OC. The aim of this study was to characterize the FGF-FGFR system, its influence on malignancy-related cell properties and its potential role as a druggable signaling pathway in OC cells. Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that expression of FGFs and FGFRs, leading to autocrine signaling loops with a strong mitogenic potential, is a common event in OC. Immunoblotting proved that the FGF signaling system is functionally active in these cells. Conditioned growth medium was able to induce phosphorylation of ERK1/2. Moreover, recombinant FGF-2 significantly elevated the growth rate in approximately 50% of the OC cell lines as demonstrated by formazan dye assay, whereas FGF-1 markedly induced migration in 66% of the cell lines. The dependency of OC cells on FGFR signaling was further evaluated by growth inhibition assays using the two small molecular FGFR inhibitors PD173074 and dovitinib (TKI-258, CHIR-258). A-2780 cells were found to be extremely sensitive to FGFR inhibition, while HEY and SKOV-3 cells showed moderate sensitivity. In contrast, OVCAR-3 cells were not inhibited by these compounds. Together, our data suggest that FGFR inhibitors reveal anticancer activity in a significant proportion of OC cells even as single drugs. Thus, combination of conventional cytotoxic intervention with blockade of the FGF-FGFR system might represent a promising future strategy for the treatment of OC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1229. doi:1538-7445.AM2012-1229