PMID- 22566604
OWN - NLM
STAT- MEDLINE
DCOM- 20120913
LR  - 20211203
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Linking)
VI  - 119
IP  - 25
DP  - 2012 Jun 21
TI  - Inhibition of the mTORC2 and chaperone pathways to treat leukemia.
PG  - 6080-8
LID - 10.1182/blood-2011-12-399519 [doi]
AB  - Constitutive activation of the kinases Akt or protein kinase C (PKC) in blood 
      cancers promotes tumor-cell proliferation and survival and is associated with 
      poor patient survival. The mammalian target of rapamycin (mTOR) complex 2 
      (mTORC2) regulates the stability of Akt and conventional PKC (cPKC; PKCalpha and 
      PKCbeta) proteins by phosphorylating the highly conserved turn motif of these 
      proteins. In cells that lack mTORC2 function, the turn motif phosphorylation of 
      Akt and cPKC is abolished and therefore Akt and cPKC protein stability is 
      impaired. However, the chaperone protein HSP90 can stabilize Akt and cPKC, 
      partially rescuing the expression of these proteins. In the present study, we 
      investigated the antitumor effects of inhibiting mTORC2 plus HSP90 in mouse and 
      human leukemia cell models and show that the HSP90 inhibitor 
      17-allylaminogeldanamycin (17-AAG) preferentially inhibits Akt and cPKC 
      expression and promotes cell death in mTORC2 deficient pre-B leukemia cells. 
      Furthermore, we show that 17-AAG selectively inhibits mTORC2 deficient leukemia 
      cell growth in vivo. Finally, we show that the mTOR inhibitors rapamycin and 
      pp242 work together with 17-AAG to inhibit leukemia cell growth to a greater 
      extent than either drug alone. These studies provide a mechanistic and clinical 
      rationale to combine mTOR inhibitors with chaperone protein inhibitors to treat 
      human blood cancers.
FAU - Zhang, Fan
AU  - Zhang F
AD  - Department of Immunobiology and Vascular Biology and Therapeutic Program, Yale 
      University School of Medicine, New Haven, CT 06520, USA.
FAU - Lazorchak, Adam S
AU  - Lazorchak AS
FAU - Liu, Dou
AU  - Liu D
FAU - Chen, Fangping
AU  - Chen F
FAU - Su, Bing
AU  - Su B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20120507
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Benzoquinones)
RN  - 0 (Crtc2 protein, mouse)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Indoles)
RN  - 0 (Lactams, Macrocyclic)
RN  - 0 (Molecular Chaperones)
RN  - 0 (Purines)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 4GY0AVT3L4 (tanespimycin)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - H5669VNZ7V (PP242)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Benzoquinones/administration & dosage
MH  - Cells, Cultured
MH  - Drug Evaluation, Preclinical
MH  - HEK293 Cells
MH  - HSP90 Heat-Shock Proteins/antagonists & inhibitors
MH  - Humans
MH  - Indoles/administration & dosage
MH  - Jurkat Cells
MH  - Lactams, Macrocyclic/administration & dosage
MH  - Leukemia/*drug therapy
MH  - Mice
MH  - Mice, Transgenic
MH  - Molecular Chaperones/*antagonists & inhibitors/metabolism
MH  - Purines/administration & dosage
MH  - Signal Transduction/drug effects/physiology
MH  - Sirolimus/administration & dosage
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
MH  - Trans-Activators/*antagonists & inhibitors/metabolism
MH  - Transcription Factors
EDAT- 2012/05/09 06:00
MHDA- 2012/09/14 06:00
CRDT- 2012/05/09 06:00
PHST- 2012/05/09 06:00 [entrez]
PHST- 2012/05/09 06:00 [pubmed]
PHST- 2012/09/14 06:00 [medline]
AID - S0006-4971(20)47652-9 [pii]
AID - 10.1182/blood-2011-12-399519 [doi]
PST - ppublish
SO  - Blood. 2012 Jun 21;119(25):6080-8. doi: 10.1182/blood-2011-12-399519. Epub 2012 
      May 7.