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Mouse avatar models of esophageal squamous cell carcinoma proved the potential for EGFR-TKI afatinib and uncovered Src family kinases involved in acquired resistance
Liu, Zhentao1; Chen, Zuhua1; Wang, Jingyuan1; Zhang, Mengqi1; Li, Zhongwu2; Wang, Shubin3; Dong, Bin2; Zhang, Cheng1; Gao, Jing1,3; Shen, Lin1,3
通讯作者Gao, Jing(1,3) ; Shen, Lin(1,3)
关键词ESCC Mouse avatar Afatinib Src family kinases Acquired resistance
刊名JOURNAL OF HEMATOLOGY & ONCOLOGY
2018-08-29
DOI10.1186/s13045-018-0651-z
11
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Oncology ; Hematology
研究领域[WOS]Oncology ; Hematology
关键词[WOS]LUNG-CANCER ; 2ND-LINE TREATMENT ; RANDOMIZED-TRIAL ; PHASE-II ; MULTICENTER ; GEFITINIB ; CETUXIMAB ; INHIBITORS ; EFFICACY ; THERAPY
英文摘要

Background: No approved targeted agents are available for esophageal squamous cell carcinoma (ESCC). Informative genomic analysis and mouse patient-derived xenografts (PDX) also called mouse avatar can greatly expedite drug discovery.

Methods: Six ESCC cell lines and 7 out of 25 PDX models derived from 188 biopsies with clear molecular features were employed to evaluate the sensitivity of several EGFR blockers in vitro and in vivo, as well as the underlying antitumor mechanisms of the most promising EGFR-TKI afatinib. Mechanisms involved in acquired resistance of afatinib were explored based on established resistant cell lines and PDX models followed by an attempt to reverse resistance.

Results: Compared with other EGFR blockers, the second-generation EGFR-TKI afatinib exerted superior antitumor effects in ESCC, and EGFR copy number gain (CNG) or overexpression was proposed to be predictive biomarkers. Afatinib played its antitumor effects by inhibiting EGFR downstream pathways, as well as inducing apoptosis and cell cycle arrest at G1. It was increased phosphorylation of Src family kinases (SFKs), rather than MET upregulation, that conferred to acquired resistance of afatinib. Dual blockade of EGFR and SFKs could overcome afatinib resistance and warrants validation in clinical practice.

Conclusion: Both ESCC cell lines and PDXs with EGFR CNG or overexpression are potential candidates for afatinib, and concomitant EGFR/SFKs inhibition could reverse afatinib-acquired resistance caused by SFKs activation in ESCC.

语种英语
WOS记录号WOS:000443361000001
通讯作者邮箱gaojing_pumc@163.com ; shenlin@bjmu.edu.cn
第一作者单位Peking Univ, Canc Hosp & Inst, Dept Gastrointestinal Oncol, Key Lab Carcinogenesis & Translat Res,Minist Educ, 52 Fucheng Rd, Beijing 100142, Peoples R China
通讯作者单位Peking Univ, Canc Hosp & Inst, Dept Gastrointestinal Oncol, Key Lab Carcinogenesis & Translat Res,Minist Educ, 52 Fucheng Rd, Beijing 100142, Peoples R China ; Peking Univ, Shenzhen Hosp, Dept Oncol, 1120 Lianhua Rd, Shenzhen 518036, Guangdong, Peoples R China
ISSN1756-8722
引用统计
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/142923
专题北京大学临床肿瘤学院_胃肠肿瘤中心
北京大学临床肿瘤学院_消化肿瘤内科
北京大学临床肿瘤学院_病理科
北京大学临床肿瘤学院_中心实验室
北京大学第一临床医学院_呼吸科
作者单位1.Peking Univ, Canc Hosp & Inst, Dept Gastrointestinal Oncol, Key Lab Carcinogenesis & Translat Res,Minist Educ, 52 Fucheng Rd, Beijing 100142, Peoples R China;
2.Peking Univ, Canc Hosp & Inst, Dept Pathol, Key Lab Carcinogenesis & Translat Res,Minist Educ, 52 Fucheng Rd, Beijing 100142, Peoples R China;
3.Peking Univ, Shenzhen Hosp, Dept Oncol, 1120 Lianhua Rd, Shenzhen 518036, Guangdong, Peoples R China
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Liu, Zhentao,Chen, Zuhua,Wang, Jingyuan,et al. Mouse avatar models of esophageal squamous cell carcinoma proved the potential for EGFR-TKI afatinib and uncovered Src family kinases involved in acquired resistance[J]. JOURNAL OF HEMATOLOGY & ONCOLOGY,2018,11.
APA Liu, Zhentao.,Chen, Zuhua.,Wang, Jingyuan.,Zhang, Mengqi.,Li, Zhongwu.,...&Shen, Lin.(2018).Mouse avatar models of esophageal squamous cell carcinoma proved the potential for EGFR-TKI afatinib and uncovered Src family kinases involved in acquired resistance.JOURNAL OF HEMATOLOGY & ONCOLOGY,11.
MLA Liu, Zhentao,et al."Mouse avatar models of esophageal squamous cell carcinoma proved the potential for EGFR-TKI afatinib and uncovered Src family kinases involved in acquired resistance".JOURNAL OF HEMATOLOGY & ONCOLOGY 11(2018).
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