Remarkable inhibition effects of afatinib alone or combining with paclitaxel in esophageal squamous cell carcinoma. Issue 9 (1st April 2021)

• Record Type: Journal Article
• Authors: Yang, Li‐Yan; Cheng, Zhi‐Jian; Liu, Zou; Wang, Di; Zhang, Na; Fan, Zhi‐Lu; Cai, Hong‐Qing; Zhang, Yu; Cai, Yan; Xu, Xin; Wang, Jin‐Hua; Du, Guan‐Hua; Hao, Jia‐Jie; Wang, Ming‐Rong
• Is Part Of: Journal of gastroenterology and hepatology. Volume 36:Issue 9(2021)
• Page Start: 2513
• Page End: 2522
• Publication Date: 2021-04-01
• Subjects: afatinib -- combination -- ESCC -- paclitaxel -- targeted therapy; Gastroenterology -- Periodicals; Digestive organs -- Diseases -- Periodicals; Liver -- Diseases -- Periodicals; Gastroenterology -- Periodicals; Liver Diseases -- Periodicals; 616.33
• DOI: 10.1111/jgh.15490
• Languages: English
• ISSNs: 0815-9319

Abstract

Abstract: 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.