FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib

Masaaki Hibi, Hiroyasu Kaneda, Junko Tanizaki, Kazuko Sakai, Yosuke Togashi, Masato Terashima, Marco Antonio De Velasco, Yoshihiko Fujita, Eri Banno, Yu Nakamura, Masayuki Takeda, Akihiko Ito, Tetsuya Mitsudomi, Kazuhiko Nakagawa, Isamu Okamoto, Kazuto Nishio

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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.

Original languageEnglish
Pages (from-to)1667-1676
Number of pages10
JournalCancer Science
Volume107
Issue number11
DOIs
Publication statusPublished - Nov 1 2016

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Fibroblast Growth Factor Receptors
Squamous Cell Carcinoma
Lung
Genes
Cell Line
Mutation
nintedanib
Recurrence
Non-Small Cell Lung Carcinoma
Clinical Trials

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Hibi, M., Kaneda, H., Tanizaki, J., Sakai, K., Togashi, Y., Terashima, M., ... Nishio, K. (2016). FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib. Cancer Science, 107(11), 1667-1676. https://doi.org/10.1111/cas.13071

FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib. / Hibi, Masaaki; Kaneda, Hiroyasu; Tanizaki, Junko; Sakai, Kazuko; Togashi, Yosuke; Terashima, Masato; De Velasco, Marco Antonio; Fujita, Yoshihiko; Banno, Eri; Nakamura, Yu; Takeda, Masayuki; Ito, Akihiko; Mitsudomi, Tetsuya; Nakagawa, Kazuhiko; Okamoto, Isamu; Nishio, Kazuto.

In: Cancer Science, Vol. 107, No. 11, 01.11.2016, p. 1667-1676.

Research output: Contribution to journalArticle

Hibi, M, Kaneda, H, Tanizaki, J, Sakai, K, Togashi, Y, Terashima, M, De Velasco, MA, Fujita, Y, Banno, E, Nakamura, Y, Takeda, M, Ito, A, Mitsudomi, T, Nakagawa, K, Okamoto, I & Nishio, K 2016, 'FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib', Cancer Science, vol. 107, no. 11, pp. 1667-1676. https://doi.org/10.1111/cas.13071
Hibi, Masaaki ; Kaneda, Hiroyasu ; Tanizaki, Junko ; Sakai, Kazuko ; Togashi, Yosuke ; Terashima, Masato ; De Velasco, Marco Antonio ; Fujita, Yoshihiko ; Banno, Eri ; Nakamura, Yu ; Takeda, Masayuki ; Ito, Akihiko ; Mitsudomi, Tetsuya ; Nakagawa, Kazuhiko ; Okamoto, Isamu ; Nishio, Kazuto. / FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib. In: Cancer Science. 2016 ; Vol. 107, No. 11. pp. 1667-1676.
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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.",
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AU - Takeda, Masayuki

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AU - Mitsudomi, Tetsuya

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