Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells

doi:10.1038/aps.2016.85

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	Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells
	Wang, Yue-qin 1; Shen, Ai-jun2 ; Sun, Jing-ya 2; Wang, Xin2 ; Liu, Hong-chun2 ; Zhang, Min-min2 ; Chen, Dan-qi3 ; Xiong, Bing3 ; Shen, Jing-kang 3; Geng, Mei-yu2
刊名	ACTA PHARMACOLOGICA SINICA
	2016-12
卷号	37 期号:12 页码:1587-1596
关键词	non-small cell lung cancer gefitinib resistance Hsp90
ISSN号	1671-4083
DOI	10.1038/aps.2016.85
文献子类	Article
英文摘要	Aim: Inhibition of heat shock protein (Hsp90) has been proven to be effective in overriding primary and acquired resistance of kinase inhibitors. In this study, we investigated the role of FS-108, a newly developed Hsp90 inhibitor, to overcome gefitinib resistance in EGFR mutant non-small cell lung cancer cells. Methods: Cell proliferation was assessed using the SRB assay. Cell cycle distribution and apoptosis were analyzed by flow cytometry. Protein expression was examined by Western blotting. The in vivo effectiveness of FS-108 was determined in an NCI-H1975 subcutaneous xenograft model. Results: FS-108 triggered obvious growth inhibition in gefitinib-resistant HCC827/GR6, NCI-H1650 and NCI-H1975 cells through inducing G(2)/M phase arrest and apoptosis. FS-108 treatment resulted in a remarkable degradation of key client proteins involved in gefitinib resistance and further abrogated their downstream signaling pathways. Interestingly, FS-108 alone exerted an identical or superior effect on circumventing gefitinib resistance compared to combined kinase inhibition. Finally, the ability of FS-108 to overcome gefitinib resistance in vivo was validated in an NCI-H1975 xenograft model. Conclusion: FS-108 is a powerful agent that impacts the survival of gefitinib-resistant cells in vitro and in vivo through targeting Hsp90.
资助项目	Natural Science Foundation of China for Innovation Research Group[81321092] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development[00000000] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020101] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020105] ; National Natural Science Foundation of China[91229205] ; National Natural Science Foundation of China[81402966] ; Shanghai Science and Technology Committee Foundation[124119b1900]
WOS关键词	TYROSINE KINASE INHIBITORS ; ACQUIRED-RESISTANCE ; MUTATIONS ; THERAPY
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
CSCD记录号	CSCD:5867011
出版者	ACTA PHARMACOLOGICA SINICA
WOS记录号	WOS:000389704500007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275782]
专题	药理学第一研究室中科院受体结构与功能重点实验室新药研究国家重点实验室药物化学研究室
通讯作者	Geng, Mei-yu; Zheng, Min; Ding, Jian
作者单位	1.China Pharmaceut Univ, Dept New Drug, Screening Ctr, Nanjing 210009, Jiangsu, Peoples R China; 2.Chinese Acad Sci, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Synthet Organ & Med Chem Lab, Shanghai 201203, Peoples R China; 4.Shanghai Jiao Tong Univ, Sch Med, Shanghai Tongren Hosp, Dept Thorac Surg, Shanghai 200336, Peoples R China
推荐引用方式 GB/T 7714	Wang, Yue-qin,Shen, Ai-jun,Sun, Jing-ya,et al. Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells[J]. ACTA PHARMACOLOGICA SINICA,2016,37(12):1587-1596.
APA	Wang, Yue-qin.,Shen, Ai-jun.,Sun, Jing-ya.,Wang, Xin.,Liu, Hong-chun.,...&Ding, Jian.(2016).Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells.ACTA PHARMACOLOGICA SINICA,37(12),1587-1596.
MLA	Wang, Yue-qin,et al."Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells".ACTA PHARMACOLOGICA SINICA 37.12(2016):1587-1596.