HSP90 inhibitor AUY922 abrogates up-regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer

doi:10.1002/ijc.28880

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药理学第一研究室

	HSP90 inhibitor AUY922 abrogates up-regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer
	Chen, Si-Meng; Guo, Chen-Liang; Shi, Jia-Jie; Xu, Yi-Chao; Chen, Yi; Shen, Yan-Yan; Su, Yi; Ding, Jian; Meng, Ling-Hua
刊名	INTERNATIONAL JOURNAL OF CANCER
	2014-11-15
卷号	135 期号:10 页码:2462-2474
关键词	mTOR kinase inhibitor HSP90 inhibitor breast cancer receptor tyrosine kinases drug combination
ISSN号	0020-7136
DOI	10.1002/ijc.28880
文献子类	Article
英文摘要	mTOR inhibition led to activation of upstream receptor tyrosine kinases (RTKs) and AKT, which may attenuate the efficacy of mTOR kinase inhibitors. We sought to discover efficient drug combination with mTOR inhibitors by elucidating the survival feedback loops induced by mTOR inhibition in breast cancer. The feedback signaling upon treatment of mTOR inhibitor AZD8055 was determined and the combinatorial activity of AZD8055 and HSP90 inhibitor AUY922 in cell signaling and proliferation were detected. Treatment of breast cancer T47D cells with AZD8055 induced activation of AKT and phosphatidylinositol 3-kinase (PI3K), which was accompanied with increase in expression of multiple upstream proteins including EGFR, HER2, HER3 and IRS-1. Different RTKs were revealed to be responsible for the reactivation of AKT by AZD8055 in different breast cancer cell lines. Down-regulation of these proteins differentially enhanced the antiproliferative activity of AZD8055. AZD8055 and AUY922 displayed synergistic effect against a panel of human breast cancer cells irrespective their genotype, which was associated with enhanced cell cycle arrest and inhibition of DNA synthesis. AUY922 destabilized multiple tested tyrosine kinases and abrogated activation of AKT induced by AZD8055. AZD8055 also inhibited up-regulation of HSP70 and HSP27 upon AUY922 treatment. Cotreatment of these two drugs demonstrated synergistic activity against triple negative MDA-MB-468 xenograft without enhanced toxicity. The combination of AZD8055 and AUY922 demonstrated synergistic activity against various types of breast cancer and established a mechanistic rationale for a combination approach using catalytic mTOR kinase inhibitor and HSP90 inhibitor in the treatment of breast cancer. What's new? The PI3K-AKT-mTOR signaling pathway, which frequently shows aberrant activation in breast cancer, is an attractive target for therapy. mTOR-targeted cancer therapy has, however, been reported to induce multiple survival feedback signals involving tyrosine kinases. Here, the authors sought to elucidate the main feedback loops induced by mTOR inhibitors in order to rationally design efficient drug combinations. They demonstrated the synergistic activity of combined HSP90 inhibitor AUY922 and mTOR kinase inhibitor AZD8055 against human breast cancers with different genotypes, both in vitro and vivo. Synergy resulted from mutual inhibition of survival feedback loops triggered by inhibition of mTOR or HSP90.
资助项目	National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program"[2012ZX09301-001] ; National Natural Science Foundation of China[81321092] ; National Natural Science Foundation of China[81173079] ; National Natural Science Foundation of China[81373445] ; National Natural Science Foundation of China[81302790] ; Knowledge Innovation Program of Chinese Academy of Sciences[KSCX2-EW-Q-3]
WOS关键词	SHOCK-PROTEIN 90 ; ADVANCED SOLID TUMORS ; CELL LUNG-CANCER ; ANTITUMOR-ACTIVITY ; MAMMALIAN TARGET ; AKT ACTIVATION ; RAPAMYCIN ; RESISTANCE ; NVP-AUY922 ; COMBINATION
WOS研究方向	Oncology
语种	英语
出版者	WILEY-BLACKWELL
WOS记录号	WOS:000341984500026
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276837]
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
通讯作者	Meng, Ling-Hua
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Div Antitumor Pharmacol, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Chen, Si-Meng,Guo, Chen-Liang,Shi, Jia-Jie,et al. HSP90 inhibitor AUY922 abrogates up-regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer[J]. INTERNATIONAL JOURNAL OF CANCER,2014,135(10):2462-2474.
APA	Chen, Si-Meng.,Guo, Chen-Liang.,Shi, Jia-Jie.,Xu, Yi-Chao.,Chen, Yi.,...&Meng, Ling-Hua.(2014).HSP90 inhibitor AUY922 abrogates up-regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer.INTERNATIONAL JOURNAL OF CANCER,135(10),2462-2474.
MLA	Chen, Si-Meng,et al."HSP90 inhibitor AUY922 abrogates up-regulation of RTKs by mTOR inhibitor AZD8055 and potentiates its antiproliferative activity in human breast cancer".INTERNATIONAL JOURNAL OF CANCER 135.10(2014):2462-2474.