Journal Article

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

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

2016

Overview

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. The angiokinase inhibitor nintedanib is a potential targeted agent for lung squamous cell carcinoma (LSCC) positive for genetic alterations affecting FGFR genes. We screened 75 LSCC specimens for FGFR alterations by next‐generation sequencing and thereby identified various such genetic changes including copy number gain, mutations, and a fusion in 15 of the 75 (20.0%) cases. Among the patients with relapse after surgery, the presence of FGFR alterations was associated with a significantly shorter overall survival.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Animals / Antitumor activity / Carcinoma, Squamous Cell - drug therapy / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - pathology / Cell growth / Cell Proliferation - drug effects / Clinical trials / Committees / Copy number / Copy number gain / DNA Copy Number Variations - genetics / Esophageal cancer / Female / FGFR1 / Fibroblast growth factor receptor 1 / Fibroblast growth factor receptor 2 / Fibroblast growth factor receptor 4 / Fibroblast growth factor receptors / Fibroblasts / Gene amplification / Humans / Immunoglobulins / Indoles - pharmacology / Indoles - therapeutic use / Kinases / Laboratory animals / Lung cancer / Lung carcinoma / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lung Neoplasms - pathology / lung squamous cell cancer / Medical prognosis / Medical research / Mice / Molecular Targeted Therapy / Mutant Proteins - genetics / Mutation / Neoplasm Recurrence, Local / next‐generation sequencing / nintedanib / Non-small cell lung carcinoma / Original / Patients / Pharmaceuticals / 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 / Research funding / Signal transduction / Squamous cell carcinoma / Surgery / Survival Analysis / Tumors / University faculty / Values / Vascular endothelial growth factor / Xenograft Model Antitumor Assays