Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy

Karin Schelch, Mir A. Hoda, Thomas Klikovits, Julia Münzker, Bahil Ghanim, Christina Wagner, Tamas Garay, Viktoria Laszlo, Ulrike Setinek, Balazs Dome, Martin Filipits, Christine Pirker, Petra Heffeter, Edgar Selzer, Jozsef Tovari, Szilvia Torok, Istvan Kenessey, Klaus Holzmann, Bettina Grasl-Kraupp, Brigitte MarianWalter Klepetko, Walter Berger, Balazs Hegedus, Michael Grusch

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27 Citations (Scopus)

Abstract

Rationale: Malignant pleural mesothelioma is an aggressive malignancy characterized by frequent resistance to chemo- and radiotherapy, poor outcome, and limited therapeutic options. Fibroblast growth factors (FGFs) and their receptors are potential targets for cancer therapy, but their significance in mesothelioma has remained largely undefined. Objectives: To investigate the antimesothelioma potential of FGF receptor 1 (FGFR1) inhibition. Methods: Expression of FGFs and their receptors was analyzed in mesothelioma cell lines and tissue specimens. Several cell models were used to investigate FGFR1 inhibition in vitro and in combination with cisplatin and irradiation. Mouse intraperitoneal xenotransplant models were used for in vivo validation. Measurements and Main Results: FGFR1, FGF2, and FGF18 were overexpressed in mesothelioma. Stimulation with FGF2 led to increased cell proliferation, migration, and transition to a more sarcomatoid phenotype in subsets of mesothelioma cell lines. In contrast, inhibition of FGFR1 by a specific kinase inhibitor or a dominant-negative FGFR1 construct led to significantly decreased proliferation, clonogenicity, migration, spheroid formation, and G1 cell cycle arrest in several mesothelioma cell lines, accompanied by apoptosis induction and decreased mitogen-activated protein kinase pathway activity. Reduced tumor growth, proliferation, mitogenic signaling, and apoptosis induction were observed in vivo. Inhibition of FGFR1 synergistically enhanced the cytotoxic effects of ionizing radiation and cisplatin. Conclusions: Our data suggest that the malignant phenotype of mesothelioma cells depends on intact FGF signals, which should be considered as therapeutic targets with a promising chemo- and radiosensitizing potential.

Original languageEnglish
Pages (from-to)763-772
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume190
Issue number7
DOIs
Publication statusPublished - Oct 1 2014

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Keywords

  • Asbestos-related malignancy
  • Combined modality therapy
  • Fibroblast growth factors
  • Molecular targeted therapy

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

Schelch, K., Hoda, M. A., Klikovits, T., Münzker, J., Ghanim, B., Wagner, C., Garay, T., Laszlo, V., Setinek, U., Dome, B., Filipits, M., Pirker, C., Heffeter, P., Selzer, E., Tovari, J., Torok, S., Kenessey, I., Holzmann, K., Grasl-Kraupp, B., ... Grusch, M. (2014). Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy. American Journal of Respiratory and Critical Care Medicine, 190(7), 763-772. https://doi.org/10.1164/rccm.201404-0658OC