Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells
Targeting Hsp90 with FS-108 circumvents gefitinib resistance in EGFR mutant non-small cell lung cancer cells
复制标题
使用 FS-108 靶向 Hsp90 可避免 EGFR 突变非小细胞肺癌细胞对吉非替尼耐药
DOI：
10.1038/aps.2016.85
复制
发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Jian Ding
中科院分区：
文献类型：
--
作者：
Yue-qin Wang;Ai-jun Shen;Jing-ya Sun;Xin Wang;Hong-chun Liu;Min-min Zhang;Dan-qi Chen;Bing Xiong;Jing-kang Shen;Mei-yu Geng;Min Zheng;Jian Ding
目的：抑制热休克蛋白（Hsp 90）已被证明是有效的克服原发性和获得性耐药的激酶抑制剂。在这项研究中，我们研究FS-108，一种新开发的热休克蛋白90抑制剂，克服吉非替尼耐药EGFR突变型非小细胞肺癌cells.Methods：细胞增殖进行了评估，使用SRB检测。流式细胞仪分析细胞周期分布及凋亡情况。Western blotting检测蛋白表达。结果：FS-10 8对吉非替尼耐药的HCC 82 7/GR 6、NCI-H16 5 0和NCI-H1975细胞均有明显的生长抑制作用，并可诱导细胞发生G2/M期阻滞和凋亡。FS-108处理导致参与吉非替尼耐药性的关键客户蛋白的显著降解，并进一步废除其下游信号传导途径。有趣的是，与组合的激酶抑制相比，单独的FS-108在规避吉非替尼耐药性方面发挥相同或上级的作用。最后，在NCI-H1975异种移植模型中验证了FS-108克服吉非替尼耐药的能力。结论：FS-108是一种强有力的药物，通过靶向Hsp 90影响吉非替尼耐药细胞在体外和体内的存活。
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.
登录
查看更多内容
影响因子：
120.1
作者：
Daniel Jones
通讯作者：
Daniel Jones
DOI：
10.1084/jem.20111694
发表时间：
2012-02-13
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Weigert O;Lane AA;Bird L;Kopp N;Chapuy B;van Bodegom D;Toms AV;Marubayashi S;Christie AL;McKeown M;Paranal RM;Bradner JE;Yoda A;Gaul C;Vangrevelinghe E;Romanet V;Murakami M;Tiedt R;Ebel N;Evrot E;De Pover A;Régnier CH;Erdmann D;Hofmann F;Eck MJ;Sallan SE;Levine RL;Kung AL;Baffert F;Radimerski T;Weinstock DM
通讯作者：
Weinstock DM
影响因子：
5.4
作者：
S. Burbridge;Simon Chowdhury;Peter Harper
通讯作者：
S. Burbridge;Simon Chowdhury;Peter Harper
影响因子：
11.2
作者：
Sawai, Ayana;Chandarlapaty, Sarat;Solit, David B.
通讯作者：
Solit, David B.
影响因子：
158.5
作者：
Kobayashi, S;Boggon, TJ;Halmos, B
通讯作者：
Halmos, B