PMID- 19383916
OWN - NLM
STAT- MEDLINE
DCOM- 20090714
LR  - 20211203
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 69
IP  - 9
DP  - 2009 May 1
TI  - Relationship of deregulated signaling converging onto mTOR with prognosis and 
      classification of lung adenocarcinoma shown by two independent in silico 
      analyses.
PG  - 4027-35
LID - 10.1158/0008-5472.CAN-08-3403 [doi]
AB  - There is marked disparity with a slight overlap among prognosis-predictive 
      signatures reported thus far for lung cancers. In this study, we aimed at linking 
      poor prognosis with particular pathways and/or functions of the gene sets 
      involved to better understand the underlying molecular characteristics associated 
      with the prognosis of lung adenocarcinomas. Gene set enrichment analysis 
      identified a gene set down-regulated by rapamycin as the most significant, 
      whereas several others responsive to withdrawal of glucose or amino acids, which 
      are related to signaling converging onto mammalian target of rapamycin (mTOR), 
      were also shown to be significantly associated, in addition to those related to 
      DNA damage response and cell cycle progression. We also used connectivity map 
      (C-MAP) analysis, an independent bioinformatics approach, to search for Food and 
      Drug Administration-approved drugs that potentially transform an unfavorable 
      signature to a favorable one. Those results identified inhibitors of 
      phosphatidylinositol 3-kinase (PI3K) and mTOR, as well as unexpected drugs such 
      as phenothiazine antipsychotics and resveratrol as potential candidates. 
      Experimental validation revealed that the latter unexpected agents also inhibited 
      signaling converging onto mTOR and exhibited antitumor activities. In addition, 
      deregulation of multiple signaling converging onto mTOR was shown to be 
      significantly associated with sensitivity to PI-103, a dual specificity PI3K/mTOR 
      inhibitor that is not contained in the C-MAP database, lending further support 
      for the connection. Our results clearly show the existence of gene set-definable, 
      intrinsic heterogeneities in lung adenocarcinomas, which seem to be related to 
      both clinical behavior and sensitivity to agents affecting the identified 
      pathways.
FAU - Ebi, Hiromichi
AU  - Ebi H
AD  - Division of Molecular Carcinogenesis, Center for Neurological Diseases and 
      Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
FAU - Tomida, Shuta
AU  - Tomida S
FAU - Takeuchi, Toshiyuki
AU  - Takeuchi T
FAU - Arima, Chinatsu
AU  - Arima C
FAU - Sato, Takahiko
AU  - Sato T
FAU - Mitsudomi, Tetsuya
AU  - Mitsudomi T
FAU - Yatabe, Yasushi
AU  - Yatabe Y
FAU - Osada, Hirotaka
AU  - Osada H
FAU - Takahashi, Takashi
AU  - Takahashi T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090421
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (CRTC2 protein, human)
RN  - 0 (Furans)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (PI103)
RN  - 0 (Proteins)
RN  - 0 (Pyridines)
RN  - 0 (Pyrimidines)
RN  - 0 (Transcription Factors)
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  - Adenocarcinoma/*genetics/*metabolism/pathology
MH  - Cell Line, Tumor
MH  - Computational Biology/methods
MH  - Furans/pharmacology
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Lung Neoplasms/*genetics/*metabolism/pathology
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Multiprotein Complexes
MH  - Oligonucleotide Array Sequence Analysis/methods
MH  - Phosphorylation
MH  - Proteins
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Pyridines/pharmacology
MH  - Pyrimidines/pharmacology
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases
MH  - Transcription Factors/antagonists & inhibitors/*metabolism
EDAT- 2009/04/23 09:00
MHDA- 2009/07/15 09:00
CRDT- 2009/04/23 09:00
PHST- 2009/04/23 09:00 [entrez]
PHST- 2009/04/23 09:00 [pubmed]
PHST- 2009/07/15 09:00 [medline]
AID - 0008-5472.CAN-08-3403 [pii]
AID - 10.1158/0008-5472.CAN-08-3403 [doi]
PST - ppublish
SO  - Cancer Res. 2009 May 1;69(9):4027-35. doi: 10.1158/0008-5472.CAN-08-3403. Epub 
      2009 Apr 21.