Molecular regulation of apoptotic machinery and lipid metabolism by mTORC1/mTORC2 dual inhibitors in preclinical models of HER2+/PIK3CAmut breast cancer

doi:10.18632/oncotarget.11490

	Molecular regulation of apoptotic machinery and lipid metabolism by mTORC1/mTORC2 dual inhibitors in preclinical models of HER2+/PIK3CAmut breast cancer
	Qian, Jianchang 1; Chen, Yaqing 1; Meng, Tao2 ; Ma, Lanping2 ; Meng, Lanfang 1; Wang, Xin2 ; Yu, Ting 2; Zask, Arie 3; Shen, Jingkang 2; Yu, Ker 1
刊名	ONCOTARGET
	2016-10-11
卷号	7 期号:41 页码:67071-67086
关键词	mTOR kinase inhibitor mTORC2 apoptosis lipid metabolism
ISSN号	1949-2553
DOI	10.18632/oncotarget.11490
文献子类	Article
英文摘要	The mechanistic target of rapamycin (mTOR) is a rational target for cancer treatment. While the mTORC1-selective rapalogs have shown significant benefits in the clinic, antitumor response may be further improved by inhibiting both mTORC1 and mTORC2. Herein, we established target profile of a novel mTOR kinase inhibitor (mTOR-KI) MTI-31 and employed it to study new therapeutic mechanism in breast cancer. MTI-31 demonstrated a potent mTOR binding affinity with >5000 fold selectivity over the related PI3K family isoforms. MTI-31 inhibited mTORC1- and mTORC2 function at <= 120 nM in cellular assays or 5 mg/kg orally in tumor-bearing mice. In a panel of breast cancer lines, the antitumor efficacy of MTI-31 was dependent on HER2+ and/or PIK3CAmut (HER2+/PIK3CAmut) status of the tumors and required mTORC2-specific modulation of Bim, MCL-1 and GSK3. Inactivation of Bim or GSK3 each attenuated apoptotic death resulting in mTOR-KI resistance. The antitumor response also required a suppression of lipid metabolism in therapy-sensitive tumors. Treatment with MTI-31 or AZD8055 substantially reduced lipogenesis and acetyl-CoA homeostasis, which was mechanistically linked to a blockade of mTORC2-dependent glucose-to-lipid conversion rate. We also found that the basal levels of carnitine palmitoyltransferase 1A and lipid catabolism were elevated in HER2+/PIK3CAmut breast cells and were inhibited upon mTOR-KI treatment. A CPT1A inhibitor etomoxir mimicked MTI-31 action in selective downregulation of cellular lipid catabolism. Co-treatments with MTI-31 and etomoxir enhanced the suppression of cyclin D1, c-Myc and cell growth in HER2+/PIK3CAmut tumors. These new mechanistic findings provide a rationale for targeting mTORC1 and mTORC2 in HER2+/PIK3CAmut breast cancer.
资助项目	Fudan University[EZF301002] ; National Science & Technology Major Project "Key New Drug Creation and Manufacturing Program" of China[2012ZX09103-101-026] ; National Natural Science Foundation of China[81273367] ; National Natural Science Foundation of China[81373442] ; National Basic Research 973 Program of China[2013CB932500]
WOS关键词	ADVANCED SOLID TUMORS ; I DOSE-ESCALATION ; MTOR COMPLEX 2 ; MULTIPLE-MYELOMA ; MAMMALIAN TARGET ; PROSTATE-CANCER ; LUNG-CANCER ; CELL-GROWTH ; RAPAMYCIN ; PATHWAY
WOS研究方向	Oncology ; Cell Biology
语种	英语
出版者	IMPACT JOURNALS LLC
WOS记录号	WOS:000387446200057
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/275858]
专题	药物化学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	Yu, Ker
作者单位	1.Fudan Univ, Dept Pharmacol, Sch Pharm, Shanghai, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Med Chem, State Key Lab Drug Res, Shanghai, Peoples R China; 3.Columbia Univ, Dept Biol Sci, New York, NY 10027 USA
推荐引用方式 GB/T 7714	Qian, Jianchang,Chen, Yaqing,Meng, Tao,et al. Molecular regulation of apoptotic machinery and lipid metabolism by mTORC1/mTORC2 dual inhibitors in preclinical models of HER2+/PIK3CAmut breast cancer[J]. ONCOTARGET,2016,7(41):67071-67086.
APA	Qian, Jianchang.,Chen, Yaqing.,Meng, Tao.,Ma, Lanping.,Meng, Lanfang.,...&Yu, Ker.(2016).Molecular regulation of apoptotic machinery and lipid metabolism by mTORC1/mTORC2 dual inhibitors in preclinical models of HER2+/PIK3CAmut breast cancer.ONCOTARGET,7(41),67071-67086.
MLA	Qian, Jianchang,et al."Molecular regulation of apoptotic machinery and lipid metabolism by mTORC1/mTORC2 dual inhibitors in preclinical models of HER2+/PIK3CAmut breast cancer".ONCOTARGET 7.41(2016):67071-67086.