title: Fibroblast growth factor receptor inhibition is active against mesothelioma and synergizes with radio- and chemotherapy.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: 1 Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, and.
authors.forename: Karin
authors.initials: K
authors.lastname: Schelch
authors.forename: Mir A
authors.initials: MA
authors.lastname: Hoda
authors.forename: Thomas
authors.initials: T
authors.lastname: Klikovits
authors.forename: Julia
authors.initials: J
authors.lastname: Münzker
authors.forename: Bahil
authors.initials: B
authors.lastname: Ghanim
authors.forename: Christina
authors.initials: C
authors.lastname: Wagner
authors.forename: Tamas
authors.initials: T
authors.lastname: Garay
authors.forename: Viktoria
authors.initials: V
authors.lastname: Laszlo
authors.forename: Ulrike
authors.initials: U
authors.lastname: Setinek
authors.forename: Balazs
authors.initials: B
authors.lastname: Dome
authors.forename: Martin
authors.initials: M
authors.lastname: Filipits
authors.forename: Christine
authors.initials: C
authors.lastname: Pirker
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.forename: Edgar
authors.initials: E
authors.lastname: Selzer
authors.forename: Jozsef
authors.initials: J
authors.lastname: Tovari
authors.forename: Szilvia
authors.initials: S
authors.lastname: Torok
authors.forename: Istvan
authors.initials: I
authors.lastname: Kenessey
authors.forename: Klaus
authors.initials: K
authors.lastname: Holzmann
authors.forename: Bettina
authors.initials: B
authors.lastname: Grasl-Kraupp
authors.forename: Brigitte
authors.initials: B
authors.lastname: Marian
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Balazs
authors.initials: B
authors.lastname: Hegedus
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D003131:Combined Modality Therapy / Q000379:methods; D004195:Disease Models, Animal; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D008654:Mesothelioma / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D000086002:Mesothelioma, Malignant; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D002945:Cisplatin
keywords: asbestos-related malignancy; combined modality therapy; fibroblast growth factors; molecular targeted therapy