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: 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
• Journal: Cancer science (Cancer Sci) Vol. 107 Issue 11 Pg. 1667-1676 (Nov 2016) ISSN: 1349-7006 [Electronic] England
• PMID: 27581340 (Publication Type: Journal Article)
• Copyright: © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Indoles
• Mutant Proteins
• FGFR1 protein, human
• FGFR2 protein, human
• FGFR3 protein, human
• FGFR4 protein, human
• Receptor, Fibroblast Growth Factor, Type 1
• Receptor, Fibroblast Growth Factor, Type 2
• Receptor, Fibroblast Growth Factor, Type 3
• Receptor, Fibroblast Growth Factor, Type 4
• nintedanib

Topics

• Animals
• Carcinoma, Squamous Cell (drug therapy, genetics, pathology)
• Cell Proliferation (drug effects)
• DNA Copy Number Variations (genetics)
• Female
• Humans
• Indoles (pharmacology, therapeutic use)
• Lung Neoplasms (drug therapy, genetics, pathology)
• Mice
• Molecular Targeted Therapy
• Mutant Proteins (genetics)
• Neoplasm Recurrence, Local
• Receptor, Fibroblast Growth Factor, Type 1 (genetics)
• Receptor, Fibroblast Growth Factor, Type 2 (genetics)
• Receptor, Fibroblast Growth Factor, Type 3 (genetics)
• Receptor, Fibroblast Growth Factor, Type 4 (genetics)
• Survival Analysis
• Xenograft Model Antitumor Assays