Relationship of Deregulated Signaling Converging onto mTOR with Prognosis and Classification of Lung Adenocarcinoma Shown by Two Independent In silico Analyses
Relationship of Deregulated Signaling Converging onto mTOR with Prognosis and Classification of Lung Adenocarcinoma Shown by Two Independent In silico Analyses
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DOI：
10.1158/0008-5472.can-08-3403
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发表时间：
2009-05-01
期刊：
影响因子：
11.2
通讯作者：
Takahashi, Takashi
中科院分区：
文献类型：
--
作者：
Ebi, Hiromichi;Tomida, Shuta;Takahashi, Takashi
迄今为止报道的肺癌的复发预测特征之间存在明显的差异和轻微的重叠。在这项研究中，我们的目的是将不良预后与特定的通路和/或相关基因集的功能联系起来，以更好地了解与肺腺癌预后相关的潜在分子特征。基因集富集分析确定了一个基因集下调雷帕霉素作为最显着的，而其他几个响应于撤回葡萄糖或氨基酸，这是有关的信号收敛到哺乳动物靶雷帕霉素（mTOR），也被证明是显着相关，除了那些相关的DNA损伤反应和细胞周期进程。我们还使用了连接图（C-MAP）分析，一种独立的生物信息学方法，来搜索食品和药物管理局批准的药物，这些药物可能会将不利的特征转化为有利的特征。这些结果确定了磷脂酰肌醇3-激酶（PI 3 K）和mTOR的抑制剂，以及意想不到的药物，如吩噻嗪类抗精神病药和白藜芦醇作为潜在的候选者。实验验证显示，后一种意想不到的试剂也抑制了会聚到mTOR上的信号传导并表现出抗肿瘤活性。此外，研究表明，融合到mTOR上的多种信号转导的失调与对PI-103的敏感性显著相关，PI-103是一种双重特异性PI 3 K/mTOR抑制剂，未包含在C-MAP数据库中，进一步支持了这种联系。我们的研究结果清楚地表明，在肺腺癌中存在基因组可定义的内在异质性，这似乎与临床行为和对影响已确定途径的药物的敏感性有关。[Cancer Res 2009;69（9）：4027-35]
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. [Cancer Res 2009;69(9):4027-35]