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.

FGFR1 amplification and FGFR gene fusion in resected squamous cell carcinoma of the lung

“…In the current study, we detected the FGFR1, FGFR2, FGFR3 gene fusions in SCCL patients and found the frequency of FGFR fusions was 3.7%, which is similar to previous studies [9]. FGFR fusions and FGFR1 amplification were mutually exclusive with activating mutations in EGFR, KRAS, BRAF and HER2, showing the driver's role of those gene alteration in cancer development.…”

“…The FGFR family, comprising FGFR1, FGFR2, FGFR3 and FGFR4, play crucial roles in cancer development and are targets for dysregulation by amplification, point mutations, or translocation [5,9,10]. Amplified FGFR1 has been reported in 20% of SCCL and inhibition of the FGFR1 pathway with FGFR inhibitors was demonstrated to lead to significant tumor shrinkage, suggesting that FGFR inhibitors might be an effective therapeutic option in SCCL with FGFR1 amplification [11,12].…”

Barcode sequencing identifies resistant mechanisms to epidermal growth factor receptor inhibitors in circulating tumor DNA of lung cancer patients

“…The adjusted read depth was log2‐transformed, and the median log2 value per gene was used for the copy number analysis. The log2 ratio cut‐off value for the copy number gain was set at 1.25 based on a previous study …”

FGFR a promising druggable target in cancer: Molecular biology and new drugs

“…The pre-clinical efficacy of Nintedanib and the prognostic role of FGFR alteration have been investigated in a recent study showing that FGFR alterations are detectable in 20% of lung squamous cell cancer (LSCC) by Next Generation Sequencing (NGS). In this study, 75 LSCC tissue specimens were evaluated, the prognosis of the specimens harboring FGFR alterations were significantly worse when treated with Nintedanib (Hibi et al, 2016). Currently, a pilot study of Nintedanib in molecularly selected patients with advanced NSCLC is ongoing.…”