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Remarkable inhibition effects of afatinib alone or combining with paclitaxel in esophageal squamous cell carcinoma
Author(s) -
Yang LiYan,
Cheng ZhiJian,
Liu Zou,
Wang Di,
Zhang Na,
Fan ZhiLu,
Cai HongQing,
Zhang Yu,
Cai Yan,
Xu Xin,
Wang JinHua,
Du GuanHua,
Hao JiaJie,
Wang MingRong
Publication year - 2021
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.15490
Subject(s) - afatinib , paclitaxel , medicine , apoptosis , cancer research , cell cycle , in vivo , flow cytometry , pharmacology , epidermal growth factor receptor , chemotherapy , cancer , immunology , biology , gefitinib , biochemistry , microbiology and biotechnology
Background and Aim Chemotherapy drugs do not work well in esophageal squamous cell carcinoma (ESCC), and none of the targeted drugs have been applied in clinic. This study aims to identify effective targeted drugs and related biomarkers for the treatment of ESCC. Methods The effect of 40 Food and Drug Administration‐approved small‐molecule inhibitors was first tested in five ESCC cell lines. CCK8 assays and xenografts derived from ESCC cell lines were performed to evaluate the anti‐ESCC effects of inhibitors or chemotherapeutic agents in vitro and in vivo , respectively. Immunohistochemistry was utilized to analyze the p‐EGFR expression in tissues. Western blot combining with gray analysis was conducted to detect the expression of interest protein. Flow cytometry and immunofluorescence assay were used to analyze apoptosis, cell cycle, and mitotic changes after drug treatment. Results Afatinib showed remarkable effects on inhibiting ESCC cells with higher expression of p‐EGFR. Results from combinatorial screening in ESCC cells expressing lower phosphorylation level of EGFR showed that paclitaxel and afatinib presented a significant synergistic inhibitory effect ( P < 0.001). Molecular analysis revealed that paclitaxel sensitized afatinib by activating EGFR, and afatinib in combination with paclitaxel effectively blocked MAPK pathway and induced G2/M cell arrest and apoptosis that is an indicator of mitotic catastrophe. Conclusions Our data demonstrate that afatinib is an effective drug for patients with ESCC expressing higher phosphorylation level of EGFR. And for patients with lower p‐EGFR in tumors, paclitaxel in combination with afatinib might be a promising therapeutic strategy in ESCC.