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

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.

PTK7, a Catalytically Inactive Receptor Tyrosine Kinase, Increases Oncogenic Phenotypes in Xenograft Tumors of Esophageal Squamous Cell Carcinoma KYSE-30 Cells

“…Various studies have shown that PTK7 and FGFR1 are significantly upregulated in ESCC tumor tissues and cell lines [6,23,54]. We also demonstrated that PTK7 plays an important role in FGFR1 activation in various ESCC cells [23].…”

Fibroblast growth factor receptor promotes progression of cutaneous squamous cell carcinoma

“…Enhanced FGFR expression and dysregulation has been identified in numerous human pathological malignancies, such as gastric, breast, lung, endometrial, and esophageal cancer . However, the role of FGFR in cSCC remains to be elucidated.…”

Therapeutic implications of fibroblast growth factor receptor inhibitors in a combination regimen for solid tumors (Review)

“…xenograft model became resistant to cetuximab, and that inhibition of FGFR2 signaling restored the sensitivity to cetuximab. Additionally, it has been identified that AZD4547 can increase sensitivity to gefitinib in TE10 and EC9706 cell lines; notably, higher expression levels of phospho-FGFR1 were observed in TE10 compared with in EC9706 cells, and in the best case, enhanced sensitivity was achieved (43).…”