title: FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib.
abstract: Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non-small cell lung cancer. We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined in vitro, and its effects on tumor formation were examined in vivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway in vitro and in vivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.
authors: Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.
authors: Masaaki
authors: M
authors: Hibi
authors: Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.|Department of Medical Oncology, Kishiwada Municipal Hospital, Kishiwada City, Japan.
authors: Hiroyasu
authors: H
authors: Kaneda
authors: Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.
authors: Junko
authors: J
authors: Tanizaki
authors: Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.
authors: Kazuko
authors: K
authors: Sakai
authors: Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.
authors: Yosuke
authors: Y
authors: Togashi
authors: Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.|Genome Center, Life Science Research Institute, Kindai University, Osaka-Sayama, Japan.
authors: Masato
authors: M
authors: Terashima
authors: Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.
authors: Marco Antonio
authors: MA
authors: De Velasco
authors: Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.
authors: Yoshihiko
authors: Y
authors: Fujita
authors: Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.
authors: Eri
authors: E
authors: Banno
authors: Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.
authors: Yu
authors: Y
authors: Nakamura
authors: Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.
authors: Masayuki
authors: M
authors: Takeda
authors: Department of Pathology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.
authors: Akihiko
authors: A
authors: Ito
authors: Department of Surgery, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.
authors: Tetsuya
authors: T
authors: Mitsudomi
authors: Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.
authors: Kazuhiko
authors: K
authors: Nakagawa
authors: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Isamu
authors: I
authors: Okamoto
authors: Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.
authors: Kazuto
authors: K
authors: Nishio
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D058990:Molecular Targeted Therapy; D050505:Mutant Proteins / Q000235:genetics; D009364:Neoplasm Recurrence, Local; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics*; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000235:genetics*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D050505:Mutant Proteins; C496348:FGFR1 protein, human; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human; C496371:FGFR4 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; D051499:Receptor, Fibroblast Growth Factor, Type 4; C530716:nintedanib
keywords: 
  FGFR1
  ; Copy number gain; lung squamous cell cancer; next-generation sequencing; nintedanib