FGFR inhibitor AZD4547 can enhance sensitivity of esophageal squamous cell carcinoma cells with epithelialmesenchymal transition to gefitinib.
Oncol Rep
; 39(5): 2270-2278, 2018 May.
Article
em En
| MEDLINE
| ID: mdl-29517107
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 (pFGFR1) 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 pFGFR1 in 87 ESCC specimens. The effects of gefitinib and FGFR inhibitor AZD4547 on ESCC cells were analyzed by CCK8 assay, flow cytometry and western blotting assays. Twentysix patients diagnosed with esophageal squamous cell carcinoma (ESCC) (29.9%) were observed with a high level of pFGFR1. The proportion of lesions located in the lower segment of the esophagus was significantly higher in the high pFGFR1 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 pFGFR1 and pAKT than that in EC9706 cells. AZD4547 and gefitinib cotreatment resulted in a significant decrease in the level of pAKT 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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Base de dados:
MEDLINE
Assunto principal:
Piperazinas
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Pirazóis
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Quinazolinas
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Benzamidas
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Neoplasias Esofágicas
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Carcinoma de Células Escamosas
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Receptor Tipo 1 de Fator de Crescimento de Fibroblastos
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Antineoplásicos
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article