Abstract 1067: Targeting the fibroblast growth factor receptor axis in malignant pleural mesothelioma

Abstract

Abstract Background: Malignant pleural mesothelioma (MPM) is an aggressive malignancy characterized by frequent resistance to chemo- and radiotherapy. Fibroblast growth factors (FGF) and their high-affinity receptors (FGFR) contribute to malignant growth in several tumor types including thoracic malignancies while a role in MPM remains widely undefined. Therefore, aim of the present study was to investigate the expression and impact of FGFs and FGFRs in MPM and to evaluate their potential suitability as new therapeutic targets. Material und Methods: Expression of all known FGF and FGFR genes was assessed by expression array analysis and confirmed by qRT PCR in MPM cell lines (n=10) and normal mesothelial cells. Selected FGFs were also investigated by immunohistochemistry on tissue samples. FGFR-specific tyrosine kinase inhibitors and an adenovirus expressing dominant-negative FGFR1 were used to block FGF signal transduction in MPM cell models. MTT and clonogenic assays as well as spheroid formation assays and videomicroscopy were performed to analyze cell growth, survival and migration. The effect on downstream signal transduction was assessed by immunoblotting with phosphorylation site-specific antibodies. Results: FGFR1 as well as the ligands FGF2 and FGF18 were highly expressed in almost all MPM cell lines investigated. Moreover, immunohistochemistry demonstrated high FGF expression also in tissue sections. Stimulation with exogenous FGF2 in contrast, led to a remarkable increase in cell migration and clonogenic growth. In contrast, inhibition of FGFR1 by the specific small molecule kinase inhibitor PD166866 lead to decreased proliferation, survival, migration and spheroid formation in the majority of cell lines tested. Adenoviral expression of dominant-negative FGFR1 further confirmed these results. In addition, concomitant FGFR inhibition increased the efficacy of currently used chemotherapeutic agents such as cisplatin. Also combination of FGFR inhibition and radiation lead to enhanced cytotoxicity. Conclusion: Taken together, these data suggest that FGFR signals contribute to proliferation, survival, migration and chemotherapy resistance of MPM cells and their inhibition should be further evaluated as a potential new treatment strategy in MPM. 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 1067. doi:1538-7445.AM2012-1067