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, B. Döme, Martin Filipits, Christine Pirker, Petra Heffeter, Edgar Selzer, J. Tóvári, Szilvia Torok, I. Kenessey, Klaus Holzmann, Bettina Grasl-Kraupp, Brigitte MarianWalter Klepetko, Walter Berger, B. Hegedűs, Michael Grusch

Research output: Contribution to journalArticle

24 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

Fingerprint

Fibroblast Growth Factor Receptors
Mesothelioma
Fibroblast Growth Factor 1
Radiotherapy
Drug Therapy
Fibroblast Growth Factor 2
Cell Line
Cisplatin
Receptor, Fibroblast Growth Factor, Type 1
Apoptosis
G1 Phase Cell Cycle Checkpoints
Phenotype
Neoplasms
Fibroblast Growth Factors
Ionizing Radiation
Mitogen-Activated Protein Kinases
Cell Movement
Phosphotransferases
Therapeutics
Cell Proliferation

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
  • Medicine(all)

Cite this

Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy. / Schelch, Karin; Hoda, Mir A.; Klikovits, Thomas; Münzker, Julia; Ghanim, Bahil; Wagner, Christina; Garay, Tamas; Laszlo, Viktoria; Setinek, Ulrike; Döme, B.; Filipits, Martin; Pirker, Christine; Heffeter, Petra; Selzer, Edgar; Tóvári, J.; Torok, Szilvia; Kenessey, I.; Holzmann, Klaus; Grasl-Kraupp, Bettina; Marian, Brigitte; Klepetko, Walter; Berger, Walter; Hegedűs, B.; Grusch, Michael.

In: American Journal of Respiratory and Critical Care Medicine, Vol. 190, No. 7, 01.10.2014, p. 763-772.

Research output: Contribution to journalArticle

Schelch, K, Hoda, MA, Klikovits, T, Münzker, J, Ghanim, B, Wagner, C, Garay, T, Laszlo, V, Setinek, U, Döme, B, Filipits, M, Pirker, C, Heffeter, P, Selzer, E, Tóvári, J, Torok, S, Kenessey, I, Holzmann, K, Grasl-Kraupp, B, Marian, B, Klepetko, W, Berger, W, Hegedűs, 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, vol. 190, no. 7, pp. 763-772. https://doi.org/10.1164/rccm.201404-0658OC
Schelch, Karin ; Hoda, Mir A. ; Klikovits, Thomas ; Münzker, Julia ; Ghanim, Bahil ; Wagner, Christina ; Garay, Tamas ; Laszlo, Viktoria ; Setinek, Ulrike ; Döme, B. ; Filipits, Martin ; Pirker, Christine ; Heffeter, Petra ; Selzer, Edgar ; Tóvári, J. ; Torok, Szilvia ; Kenessey, I. ; Holzmann, Klaus ; Grasl-Kraupp, Bettina ; Marian, Brigitte ; Klepetko, Walter ; Berger, Walter ; Hegedűs, B. ; Grusch, Michael. / Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy. In: American Journal of Respiratory and Critical Care Medicine. 2014 ; Vol. 190, No. 7. pp. 763-772.
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AU - Schelch, Karin

AU - Hoda, Mir A.

AU - Klikovits, Thomas

AU - Münzker, Julia

AU - Ghanim, Bahil

AU - Wagner, Christina

AU - Garay, Tamas

AU - Laszlo, Viktoria

AU - Setinek, Ulrike

AU - Döme, B.

AU - Filipits, Martin

AU - Pirker, Christine

AU - Heffeter, Petra

AU - Selzer, Edgar

AU - Tóvári, J.

AU - Torok, Szilvia

AU - Kenessey, I.

AU - Holzmann, Klaus

AU - Grasl-Kraupp, Bettina

AU - Marian, Brigitte

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AU - Berger, Walter

AU - Hegedűs, B.

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