PMID- 17218776
OWN - NLM
STAT- MEDLINE
DCOM- 20070831
LR  - 20211203
IS  - 1538-4047 (Print)
IS  - 1538-4047 (Linking)
VI  - 6
IP  - 2
DP  - 2007 Feb
TI  - Combining an mTOR antagonist and receptor tyrosine kinase inhibitors for the 
      treatment of prostate cancer.
PG  - 195-201
AB  - Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway is a 
      potentially useful therapeutic strategy in the treatment of advanced prostate 
      cancer. However mTOR antagonists used as single agents are not likely to result 
      in dramatic clinical responses, so that it is useful to identify prospective 
      agents that might be useful in combination. We treated CWR22Rv1 and LNCaP 
      prostate cancer cells with an mTOR inhibitor, rapamycin, alone, or in combination 
      with either of two receptor protein kinase (RTK) inhibitors. We assessed the 
      effects of these treatments on cell survival and activation of down-stream mTOR 
      target proteins. Treatment with either PD16839, an EGFr antagonist, or imatinib 
      mesylate (Gleevec), a PDGFr, c-kit and bcr/abl antagonist, enhanced the 
      anti-proliferative effects of rapamycin. We therefore assessed the effects of 
      treatment with the RTK antagonist alone and in combination with rapamycin on mTOR 
      targeted proteins. RTK antagonists alone had no effect or paradoxically increased 
      phosphorylation of the mTOR targeted proteins, p70 S6 kinase and ribosomal S6. In 
      contrast, when these cells were treated with either RTK antagonist in the 
      presence of rapamycin, there was a dramatic decrease in phosphorylation of these 
      two mTOR-targeted proteins. These effects were not mediated through phospho-AKT. 
      Since two separate RTK antagonists had additive antiproliferative effects in 
      combination with an mTOR antagonist and were associated with a dramatic decrease 
      in mTOR targeted proteins in cells with or without PTEN expression, the strategy 
      deserves further evaluation for the treatment of prostate cancer.
FAU - Masiello, David
AU  - Masiello D
AD  - Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical 
      Center, Harvard Institutes of Medicine, 300 Brookline Avenue, Boston, MA 02215, 
      USA.
FAU - Mohi, M Golam
AU  - Mohi MG
FAU - McKnight, Nicole C
AU  - McKnight NC
FAU - Smith, Bradley
AU  - Smith B
FAU - Neel, Ben G
AU  - Neel BG
FAU - Balk, Steven P
AU  - Balk SP
FAU - Bubley, Glenn J
AU  - Bubley GJ
LA  - eng
GR  - P01 DK 50654/DK/NIDDK NIH HHS/United States
GR  - P50 CA 90381/CA/NCI NIH HHS/United States
GR  - R01 DK 50693/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20070207
PL  - United States
TA  - Cancer Biol Ther
JT  - Cancer biology & therapy
JID - 101137842
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzamides)
RN  - 0 (Piperazines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - 8A1O1M485B (Imatinib Mesylate)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Antineoplastic Agents/*pharmacology
MH  - Benzamides
MH  - Blotting, Western
MH  - Cell Line, Tumor
MH  - Cell Proliferation/*drug effects
MH  - Cell Survival/drug effects
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Imatinib Mesylate
MH  - Male
MH  - Piperazines/pharmacology
MH  - Prostatic Neoplasms/*drug therapy
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Protein Kinases
MH  - Pyrimidines/pharmacology
MH  - Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
MH  - Sirolimus/*pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Treatment Outcome
EDAT- 2007/01/16 09:00
MHDA- 2007/09/01 09:00
CRDT- 2007/01/16 09:00
PHST- 2007/01/16 09:00 [pubmed]
PHST- 2007/09/01 09:00 [medline]
PHST- 2007/01/16 09:00 [entrez]
AID - 3588 [pii]
AID - 10.4161/cbt.6.2.3588 [doi]
PST - ppublish
SO  - Cancer Biol Ther. 2007 Feb;6(2):195-201. doi: 10.4161/cbt.6.2.3588. Epub 2007 Feb 
      7.