PMID- 27581340 OWN - NLM STAT- MEDLINE DCOM- 20170214 LR - 20210109 IS - 1349-7006 (Electronic) IS - 1347-9032 (Print) IS - 1347-9032 (Linking) VI - 107 IP - 11 DP - 2016 Nov TI - FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib. PG - 1667-1676 LID - 10.1111/cas.13071 [doi] AB - 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. CI - (c) 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. FAU - Hibi, Masaaki AU - Hibi M AD - Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. FAU - Kaneda, Hiroyasu AU - Kaneda H AD - Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. AD - Department of Medical Oncology, Kishiwada Municipal Hospital, Kishiwada City, Japan. FAU - Tanizaki, Junko AU - Tanizaki J AD - Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. FAU - Sakai, Kazuko AU - Sakai K AD - Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. FAU - Togashi, Yosuke AU - Togashi Y AD - Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. FAU - Terashima, Masato AU - Terashima M AD - Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. AD - Genome Center, Life Science Research Institute, Kindai University, Osaka-Sayama, Japan. FAU - De Velasco, Marco Antonio AU - De Velasco MA AD - Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. FAU - Fujita, Yoshihiko AU - Fujita Y AD - Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. FAU - Banno, Eri AU - Banno E AD - Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. FAU - Nakamura, Yu AU - Nakamura Y AD - Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. FAU - Takeda, Masayuki AU - Takeda M AD - Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. FAU - Ito, Akihiko AU - Ito A AD - Department of Pathology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. FAU - Mitsudomi, Tetsuya AU - Mitsudomi T AD - Department of Surgery, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. FAU - Nakagawa, Kazuhiko AU - Nakagawa K AD - Department of Medical Oncology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. FAU - Okamoto, Isamu AU - Okamoto I AD - Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. FAU - Nishio, Kazuto AU - Nishio K AD - Department of Genome Biology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan. LA - eng SI - GENBANK/NM_023110 SI - GENBANK/NM_001174067 SI - GENBANK/NM_000141 SI - GENBANK/NM_000142 SI - GENBANK/NM_022963 PT - Journal Article PL - England TA - Cancer Sci JT - Cancer science JID - 101168776 RN - 0 (Indoles) RN - 0 (Mutant Proteins) RN - EC 2.7.10.1 (FGFR1 protein, human) RN - EC 2.7.10.1 (FGFR2 protein, human) RN - EC 2.7.10.1 (FGFR3 protein, human) RN - EC 2.7.10.1 (FGFR4 protein, human) RN - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1) RN - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 2) RN - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 3) RN - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 4) RN - G6HRD2P839 (nintedanib) SB - IM MH - Animals MH - Carcinoma, Squamous Cell/drug therapy/*genetics/pathology MH - Cell Proliferation/drug effects MH - DNA Copy Number Variations/genetics MH - Female MH - Humans MH - Indoles/*pharmacology/*therapeutic use MH - Lung Neoplasms/drug therapy/*genetics/pathology MH - Mice MH - Molecular Targeted Therapy MH - Mutant Proteins/genetics MH - Neoplasm Recurrence, Local MH - Receptor, Fibroblast Growth Factor, Type 1/*genetics MH - Receptor, Fibroblast Growth Factor, Type 2/*genetics MH - Receptor, Fibroblast Growth Factor, Type 3/*genetics MH - Receptor, Fibroblast Growth Factor, Type 4/*genetics MH - Survival Analysis MH - Xenograft Model Antitumor Assays PMC - PMC5132273 OTO - NOTNLM OT - FGFR1 OT - Copy number gain OT - lung squamous cell cancer OT - next-generation sequencing OT - nintedanib EDAT- 2016/09/02 06:00 MHDA- 2017/02/15 06:00 PMCR- 2016/11/01 CRDT- 2016/09/02 06:00 PHST- 2016/04/14 00:00 [received] PHST- 2016/08/22 00:00 [revised] PHST- 2016/08/30 00:00 [accepted] PHST- 2016/09/02 06:00 [pubmed] PHST- 2017/02/15 06:00 [medline] PHST- 2016/09/02 06:00 [entrez] PHST- 2016/11/01 00:00 [pmc-release] AID - CAS13071 [pii] AID - 10.1111/cas.13071 [doi] PST - ppublish SO - Cancer Sci. 2016 Nov;107(11):1667-1676. doi: 10.1111/cas.13071.