title: Nonamplified FGFR1 is a growth driver in malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is associated with asbestos exposure and is a cancer that has not been significantly affected by small molecule-based targeted therapeutics. Previously, we demonstrated the existence of functional subsets of lung cancer and head and neck squamous cell carcinoma (HNSCC) cell lines in which fibroblast growth factor receptor (FGFR) autocrine signaling functions as a nonmutated growth pathway. In a panel of pleural mesothelioma cell lines, FGFR1 and FGF2 were coexpressed in three of seven cell lines and were significantly associated with sensitivity to the FGFR-active tyrosine kinase inhibitor (TKI), ponatinib, both in vitro and in vivo using orthotopically propagated xenografts. Furthermore, RNAi-mediated silencing confirmed the requirement for FGFR1 in specific mesothelioma cells and sensitivity to the FGF ligand trap, FP-1039, validated the requirement for autocrine FGFs. None of the FGFR1-dependent mesothelioma cells exhibited increased FGFR1 gene copy number, based on a FISH assay, indicating that increased FGFR1 transcript and protein expression were not mediated by gene amplification. Elevated FGFR1 mRNA was detected in a subset of primary MPM clinical specimens and like MPM cells; none harbored increased FGFR1 gene copy number. These results indicate that autocrine signaling through FGFR1 represents a targetable therapeutic pathway in MPM and that biomarkers distinct from increased FGFR1 gene copy number such as FGFR1 mRNA would be required to identify patients with MPM bearing tumors driven by FGFR1 activity.
  
  
  CONCLUSIONS
  FGFR1 is a viable therapeutic target in a subset of MPMs, but FGFR TKI-responsive tumors will need to be selected by a biomarker distinct from increased FGFR1 gene copy number, possibly FGFR1 mRNA or protein levels.
authors: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Lindsay A
authors: LA
authors: Marek
authors: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Trista K
authors: TK
authors: Hinz
authors: Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
authors: Anne
authors: A
authors: von Mässenhausen
authors: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Kyle A
authors: KA
authors: Olszewski
authors: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Emily K
authors: EK
authors: Kleczko
authors: Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
authors: Diana
authors: D
authors: Boehm
authors: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Mary C
authors: MC
authors: Weiser-Evans
authors: Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors: Raphael A
authors: RA
authors: Nemenoff
authors: Department of Thoracic Surgery, Thoraxklinik at Heidelberg University, Heidelberg, Germany.
authors: Hans
authors: H
authors: Hoffmann
authors: Institute for Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Arne
authors: A
authors: Warth
authors: ARIAD Pharmaceuticals, Inc., Cambridge, Massachusetts.
authors: Joseph M
authors: JM
authors: Gozgit
authors: Department of Prostate Cancer Research, Institute of Pathology, University Hospital of Bonn, Bonn, Germany.
authors: Sven
authors: S
authors: Perner
authors: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. lynn.heasley@ucdenver.edu.
authors: Lynn E
authors: LE
authors: Heasley
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002999:Clone Cells; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005784:Gene Amplification; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D008819:Mice, Nude; D010997:Pleural Neoplasms / Q000235:genetics* / Q000473:pathology*; D011724:Pyridazines / Q000494:pharmacology; D034622:RNA Interference; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D007093:Imidazoles; D011724:Pyridazines; D016222:Fibroblast Growth Factor 2; C545373:ponatinib; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048049:Extracellular Signal-Regulated MAP Kinases