title: Relationship of deregulated signaling converging onto mTOR with prognosis and classification of lung adenocarcinoma shown by two independent in silico analyses.
abstract: 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.
authors.affiliation: Division of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Ebi
authors.forename: Shuta
authors.initials: S
authors.lastname: Tomida
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Arima
authors.forename: Takahiko
authors.initials: T
authors.lastname: Sato
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Osada
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D005663:Furans / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010766:Phosphorylation; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C493245:CRTC2 protein, human; D005663:Furans; D046912:Multiprotein Complexes; C522973:PI103; D011506:Proteins; D011725:Pyridines; D011743:Pyrimidines; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus