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

作者：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

来源：CANCER SCIENCE, 2016, 107(11): 1667-1676.

DOI：10.1111/cas.13071

• Copy number gain
• FGFR1
• lung squamous cell cancer
• next-generation sequencing
• nintedanib

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 invitro, and its effects on tumor formation were examined invivo. 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 invitro and invivo. 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.

• 出版日期2016-11