PMID- 27563814
OWN - NLM
STAT- MEDLINE
DCOM- 20180222
LR  - 20211204
IS  - 1949-2553 (Electronic)
IS  - 1949-2553 (Linking)
VI  - 7
IP  - 41
DP  - 2016 Oct 11
TI  - Molecular regulation of apoptotic machinery and lipid metabolism by mTORC1/mTORC2 
      dual inhibitors in preclinical models of HER2+/PIK3CAmut breast cancer.
PG  - 67071-67086
LID - 10.18632/oncotarget.11490 [doi]
AB  - 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.
FAU - Qian, Jianchang
AU  - Qian J
AD  - Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.
FAU - Chen, Yaqing
AU  - Chen Y
AD  - Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.
FAU - Meng, Tao
AU  - Meng T
AD  - Department of Medicinal Chemistry, State Key Laboratory of Drug Research, 
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 
      China.
FAU - Ma, Lanping
AU  - Ma L
AD  - Department of Medicinal Chemistry, State Key Laboratory of Drug Research, 
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 
      China.
FAU - Meng, Lanfang
AU  - Meng L
AD  - Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.
FAU - Wang, Xin
AU  - Wang X
AD  - Department of Medicinal Chemistry, State Key Laboratory of Drug Research, 
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 
      China.
FAU - Yu, Ting
AU  - Yu T
AD  - Department of Medicinal Chemistry, State Key Laboratory of Drug Research, 
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 
      China.
FAU - Zask, Arie
AU  - Zask A
AD  - Department of Biological Sciences, Columbia University, New York, NY, USA.
FAU - Shen, Jingkang
AU  - Shen J
AD  - Department of Medicinal Chemistry, State Key Laboratory of Drug Research, 
      Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 
      China.
FAU - Yu, Ker
AU  - Yu K
AD  - Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Oncotarget
JT  - Oncotarget
JID - 101532965
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Breast Neoplasms/genetics/metabolism/*pathology
MH  - Cell Proliferation/drug effects
MH  - Class I Phosphatidylinositol 3-Kinases/genetics
MH  - Female
MH  - Humans
MH  - Lipid Metabolism/*drug effects
MH  - Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors
MH  - Mechanistic Target of Rapamycin Complex 2/antagonists & inhibitors
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Receptor, ErbB-2/genetics
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors
MH  - Xenograft Model Antitumor Assays
PMC - PMC5341858
OTO - NOTNLM
OT  - apoptosis
OT  - lipid metabolism
OT  - mTOR kinase inhibitor
OT  - mTORC2
COIS- CONFLICTS OF INTEREST The authors declare no conflict of interest.
EDAT- 2016/08/27 06:00
MHDA- 2018/02/23 06:00
PMCR- 2016/10/11
CRDT- 2016/08/27 06:00
PHST- 2016/03/23 00:00 [received]
PHST- 2016/08/09 00:00 [accepted]
PHST- 2016/08/27 06:00 [pubmed]
PHST- 2018/02/23 06:00 [medline]
PHST- 2016/08/27 06:00 [entrez]
PHST- 2016/10/11 00:00 [pmc-release]
AID - 11490 [pii]
AID - 10.18632/oncotarget.11490 [doi]
PST - ppublish
SO  - Oncotarget. 2016 Oct 11;7(41):67071-67086. doi: 10.18632/oncotarget.11490.