FGFR inhibitor AZD4547 can enhance sensitivity of esophageal squamous cell carcinoma cells with epithelial‑mesenchymal transition to gefitinib

Luo,Hong; Quan,Jin; Xiao,He; Luo,Jia; Zhang,Qin; Pi,Guocheng; Ye,Yunfei; He,Rong; Liu,Yun; Su,Xiaona; Zhao,Lianhua; Wang,Ge

doi:10.3892/or.2018.6304

FGFR inhibitor AZD4547 can enhance sensitivity of esophageal squamous cell carcinoma cells with epithelial‑mesenchymal transition to gefitinib

Authors:
- Hong Luo
- Jin Quan
- He Xiao
- Jia Luo
- Qin Zhang
- Guocheng Pi
- Yunfei Ye
- Rong He
- Yun Liu
- Xiaona Su
- Lianhua Zhao
- Ge Wang
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Affiliations: Cancer Center, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042, P.R. China, Department of Oncology, The Central Hospital of Jiangjin, Chongqing 402260, P.R. China, Department of Pathology, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042, P.R. China
Published online on: March 8, 2018 https://doi.org/10.3892/or.2018.6304
Pages: 2270-2278

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Abstract

Activation of fibroblast growth factor receptor (FGFR) signaling occurs in various cancers, including esophageal squamous cell carcinoma (ESCC), however, the effect of targeting FGFR in ESCC is not clear. Herein, we examined the phosphorylation level of FGFR1Y654 (p‑FGFR1) in ESCC cell lines and tumor tissues, as well as the cancer cell killing effects of gefitinib and FGFR inhibitor AZD4547 in combination form or alone in ESCC cells. Immunohistochemistry staining was used to detect the expression level of p‑FGFR1 in 87 ESCC specimens. The effects of gefitinib and FGFR inhibitor AZD4547 on ESCC cells were analyzed by CCK‑8 assay, flow cytometry and western blotting assays. Twenty‑six patients diagnosed with esophageal squamous cell carcinoma (ESCC) (29.9%) were observed with a high level of p‑FGFR1. The proportion of lesions located in the lower segment of the esophagus was significantly higher in the high p‑FGFR1 level group (26.9 vs. 8.2%, P=0.003). The IC50 values of gefitinib alone and in combination with 500 nM AZD4547 were 22.9±2.1 and 4.13±0.12 µM in TE10 cells, and 9.85±5.5 and 3.21±0.76 µM in EC9706 cells, respectively. The combination of AZD4547 and gefitinib induced robust apoptosis and decreased clone formation ability compared to gefitinib monotherapy in the TE10 cells. TE10 cells exhibited a mesenchymal phenotype, with a higher level of p‑FGFR1 and p‑AKT than that in EC9706 cells. AZD4547 and gefitinib co‑treatment resulted in a significant decrease in the level of p‑AKT in TE10 cells and a complete inhibition of phosphorylation of ERK1/2 in EC9706 cells. Collectively, AZD4547 can improve sensitivity of ESCC cells to gefitinib.

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