PMID- 21834980
OWN - NLM
STAT- MEDLINE
DCOM- 20111122
LR  - 20211203
IS  - 1479-5876 (Electronic)
IS  - 1479-5876 (Linking)
VI  - 9
DP  - 2011 Aug 11
TI  - Characterization and targeting of phosphatidylinositol-3 kinase (PI3K) and 
      mammalian target of rapamycin (mTOR) in renal cell cancer.
PG  - 133
LID - 10.1186/1479-5876-9-133 [doi]
AB  - BACKGROUND: PI3K and mTOR are key components of signal transduction pathways 
      critical for cell survival. Numerous PI3K inhibitors have entered clinical 
      trials, while mTOR is the target of approved drugs for metastatic renal cell 
      carcinoma (RCC). We characterized expression of p85 and p110alpha PI3K subunits and 
      mTOR in RCC specimens and assessed pharmacologic co-targeting of these molecules 
      in vitro. METHODS: We employed tissue microarrays containing 330 nephrectomy 
      cases using a novel immunofluorescence-based method of Automated Quantitative 
      Analysis (AQUA) of in situ protein expression. In RCC cell lines we assessed 
      synergism between PI3K and mTOR inhibitors and activity of NVP-BEZ235, which 
      co-targets PI3K and mTOR. RESULTS: p85 expression was associated with high stage 
      and grade (P < 0.0001 for both). High p85 and high mTOR expression were strongly 
      associated with decreased survival, and high p85 was independently prognostic on 
      multi-variable analysis. Strong co-expression of both PI3K subunits and mTOR was 
      found in the human specimens. The PI3K inhibitor LY294002 and rapamycin were 
      highly synergistic in all six RCC cell lines studied. Similar synergism was seen 
      with all rapamycin concentrations used. NVP-BEZ235 inhibited RCC cell growth in 
      vitro with IC(50)s in the low etaM range and resultant PARP cleavage. CONCLUSIONS: 
      High PI3K and mTOR expression in RCC defines populations with decreased survival, 
      suggesting that they are good drug targets in RCC. These targets tend to be 
      co-expressed, and co-targeting these molecules is synergistic. NVP-BEZ235 is 
      active in RCC cells in vitro; suggesting that concurrent PI3K and mTOR targeting 
      in RCC warrants further investigation.
FAU - Elfiky, Aymen A
AU  - Elfiky AA
AD  - Division of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, 
      United States of America.
FAU - Aziz, Saadia A
AU  - Aziz SA
FAU - Conrad, Patricia J
AU  - Conrad PJ
FAU - Siddiqui, Summar
AU  - Siddiqui S
FAU - Hackl, Wolfgang
AU  - Hackl W
FAU - Maira, Michel
AU  - Maira M
FAU - Robert, Camp L
AU  - Robert CL
FAU - Kluger, Harriet M
AU  - Kluger HM
LA  - eng
GR  - R0-1 CA129034/CA/NCI NIH HHS/United States
GR  - R21 CA116265/CA/NCI NIH HHS/United States
GR  - R0-1 R0-1 CA158167/CA/NCI NIH HHS/United States
GR  - R01 CA129034/CA/NCI NIH HHS/United States
GR  - R01 CA158167/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 - 20110811
PL  - England
TA  - J Transl Med
JT  - Journal of translational medicine
JID - 101190741
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Chromones)
RN  - 0 (Imidazoles)
RN  - 0 (Morpholines)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - RUJ6Z9Y0DT (dactolisib)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Apoptosis/drug effects
MH  - Automation
MH  - Biomarkers, Tumor/metabolism
MH  - Carcinoma, Renal Cell/*enzymology/pathology
MH  - Cell Line, Tumor
MH  - Chromones/pharmacology
MH  - Drug Synergism
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - Inhibitory Concentration 50
MH  - Kidney Neoplasms/*enzymology/pathology
MH  - *Molecular Targeted Therapy
MH  - Morpholines/pharmacology
MH  - Multivariate Analysis
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Quinolines/pharmacology
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
PMC - PMC3173341
EDAT- 2011/08/13 06:00
MHDA- 2011/12/13 00:00
PMCR- 2011/08/11
CRDT- 2011/08/13 06:00
PHST- 2011/02/10 00:00 [received]
PHST- 2011/08/11 00:00 [accepted]
PHST- 2011/08/13 06:00 [entrez]
PHST- 2011/08/13 06:00 [pubmed]
PHST- 2011/12/13 00:00 [medline]
PHST- 2011/08/11 00:00 [pmc-release]
AID - 1479-5876-9-133 [pii]
AID - 10.1186/1479-5876-9-133 [doi]
PST - epublish
SO  - J Transl Med. 2011 Aug 11;9:133. doi: 10.1186/1479-5876-9-133.