PMID- 22045983
OWN - NLM
STAT- MEDLINE
DCOM- 20120320
LR  - 20211203
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 118
IP  - 26
DP  - 2011 Dec 22
TI  - Defining the role of TORC1/2 in multiple myeloma.
PG  - 6860-70
LID - 10.1182/blood-2011-03-342394 [doi]
AB  - Mammalian target of rapamycin (mTOR) is a downstream serine/threonine kinase of 
      the PI3K/Akt pathway that integrates signals from the tumor microenvironment to 
      regulate multiple cellular processes. Rapamycin and its analogs have not shown 
      significant activity in multiple myeloma (MM), likely because of the lack of 
      inhibition of TORC2. In the present study, we investigated the baseline activity 
      of the PI3K/Akt/mTOR pathway TORC1/2 in MM cell lines with different genetic 
      abnormalities. TORC1/2 knock-down led to significant inhibition of the 
      proliferation of MM cells, even in the presence of BM stromal cells. We also 
      tested INK128, a dual TORC1/2 inhibitor, as a new therapeutic agent against these 
      MM cell lines. We showed that dual TORC1/2 inhibition is much more active than 
      TORC1 inhibition alone (rapamycin), even in the presence of cytokines or stromal 
      cells. In vitro and in vivo studies showed that p-4EBP1 and p-Akt inhibition 
      could be predictive markers of TORC2 inhibition in MM cell lines. Dual TORC1/2 
      inhibition showed better inhibition of adhesion to BM microenvironmental cells 
      and inhibition of homing in vivo. These studies form the basis for further 
      clinical testing of TORC1/2 inhibitors in MM.
FAU - Maiso, Patricia
AU  - Maiso P
AD  - Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
FAU - Liu, Yi
AU  - Liu Y
FAU - Morgan, Brittany
AU  - Morgan B
FAU - Azab, Abdel Kareem
AU  - Azab AK
FAU - Ren, Pingda
AU  - Ren P
FAU - Martin, Michel B
AU  - Martin MB
FAU - Zhang, Yong
AU  - Zhang Y
FAU - Liu, Yang
AU  - Liu Y
FAU - Sacco, Antonio
AU  - Sacco A
FAU - Ngo, Hai
AU  - Ngo H
FAU - Azab, Feda
AU  - Azab F
FAU - Quang, Phong
AU  - Quang P
FAU - Rodig, Scott J
AU  - Rodig SJ
FAU - Lin, Charles P
AU  - Lin CP
FAU - Roccaro, Aldo M
AU  - Roccaro AM
FAU - Rommel, Christian
AU  - Rommel C
FAU - Ghobrial, Irene M
AU  - Ghobrial IM
LA  - eng
GR  - R01 CA125690/CA/NCI NIH HHS/United States
GR  - R01CA125690-01/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20111101
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Carrier Proteins)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (EIF4EBP1 protein, human)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phosphoproteins)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proteins)
RN  - 0 (RICTOR protein, human)
RN  - 0 (RPTOR protein, human)
RN  - 0 (Rapamycin-Insensitive Companion of mTOR Protein)
RN  - 0 (Regulatory-Associated Protein of mTOR)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/antagonists & inhibitors/genetics/metabolism
MH  - Animals
MH  - Antibiotics, Antineoplastic/pharmacology
MH  - Apoptosis/drug effects
MH  - Blotting, Western
MH  - Carrier Proteins/antagonists & inhibitors/genetics/metabolism
MH  - Cell Cycle Proteins
MH  - Cell Line
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Mice, SCID
MH  - Multiple Myeloma/drug therapy/*metabolism/pathology
MH  - Multiprotein Complexes
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphoproteins/metabolism
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Proteins/antagonists & inhibitors/genetics/*metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - RNA Interference
MH  - Rapamycin-Insensitive Companion of mTOR Protein
MH  - Regulatory-Associated Protein of mTOR
MH  - Signal Transduction/drug effects
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/genetics/metabolism
MH  - Xenograft Model Antitumor Assays
PMC - PMC3245208
EDAT- 2011/11/03 06:00
MHDA- 2012/03/21 06:00
PMCR- 2012/12/22
CRDT- 2011/11/03 06:00
PHST- 2011/11/03 06:00 [entrez]
PHST- 2011/11/03 06:00 [pubmed]
PHST- 2012/03/21 06:00 [medline]
PHST- 2012/12/22 00:00 [pmc-release]
AID - S0006-4971(20)40242-3 [pii]
AID - 2011/342394 [pii]
AID - 10.1182/blood-2011-03-342394 [doi]
PST - ppublish
SO  - Blood. 2011 Dec 22;118(26):6860-70. doi: 10.1182/blood-2011-03-342394. Epub 2011 
      Nov 1.