title: FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers.
abstract: OBJECTIVE
  FGFR1 copy-number gain (CNG) occurs in head and neck squamous cell cancers (HNSCC) and is used for patient selection in FGFR-specific inhibitor clinical trials. This study explores FGFR1 mRNA and protein levels in HNSCC cell lines, primary tumors, and patient-derived xenografts (PDX) as predictors of sensitivity to the FGFR inhibitor, NVP-BGJ398.
  
  
  METHODS
  FGFR1 status, expression levels, and BGJ398 sensitive growth were measured in 12 HNSCC cell lines. Primary HNSCCs (n = 353) were assessed for FGFR1 CNG and mRNA levels, and HNSCC TCGA data were interrogated as an independent sample set. HNSCC PDXs (n = 39) were submitted to FGFR1 copy-number detection and mRNA assays to identify putative FGFR1-dependent tumors.
  
  
  RESULTS
  Cell line sensitivity to BGJ398 is associated with FGFR1 mRNA and protein levels, not FGFR1 CNG. Thirty-one percent of primary HNSCC tumors expressed FGFR1 mRNA, 18% exhibited FGFR1 CNG, 35% of amplified tumors were also positive for FGFR1 mRNA. This relationship was confirmed with the TCGA dataset. Using high FGFR1 mRNA for selection, 2 HNSCC PDXs were identified, one of which also exhibited FGFR1 CNG. The nonamplified tumor with high mRNA levels exhibited in vivo sensitivity to BGJ398.
  
  
  CONCLUSIONS
  FGFR1 expression associates with BGJ398 sensitivity in HNSCC cell lines and predicts tyrosine kinase inhibitor sensitivity in PDXs. Our results support FGFR1 mRNA or protein expression, rather than FGFR1 CNG as a predictive biomarker for the response to FGFR inhibitors in a subset of patients suffering from HNSCC.
authors.affiliation: Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Göke
authors.affiliation: Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Franzen
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Trista K
authors.initials: TK
authors.lastname: Hinz
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Marek
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Petros
authors.initials: P
authors.lastname: Yoon
authors.affiliation: Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Bode
authors.affiliation: Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: von Maessenhausen
authors.affiliation: Department of Internal Medicine, Philipps-University of Marburg, Marburg, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Lankat-Buttgereit
authors.affiliation: Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Göke
authors.affiliation: Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Golletz
authors.affiliation: Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Kirsten
authors.affiliation: Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Boehm
authors.affiliation: Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany.
authors.forename: Wenzel
authors.initials: W
authors.lastname: Vogel
authors.affiliation: Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Kleczko
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Eagles
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.affiliation: Department of Otorhinolaryngology/Head and Neck Surgery, University of Bonn, Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Van Bremen
authors.affiliation: Department of Otorhinolaryngology/Head and Neck Surgery, University of Bonn, Bonn, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Bootz
authors.affiliation: Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Department of Otorhinolaryngology/Head and Neck Surgery, University of Bonn, Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schroeck
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Aik-Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Otolaryngology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: Department of Internal Medicine, Philipps-University of Marburg, Marburg, Germany. VA Eastern Colorado Healthcare System, Denver, Colorado.
authors.forename: Lynn E
authors.initials: LE
authors.lastname: Heasley
authors.affiliation: Section of Prostate Cancer Research, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. Institute of Pathology, University Hospital of Bonn, Center for Integrated Oncology Cologne-Bonn, Bonn, Germany. sven.perner1972@googlemail.com.
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; C568950:infigratinib; D051496:Receptor, Fibroblast Growth Factor, Type 1