Relationship of Deregulated Signaling Converging onto mTOR with Prognosis and Classification of Lung Adenocarcinoma Shown by Two Independent <i>In silico</i> Analyses

Ebi, Hiromichi; Tomida, Shuta; Takeuchi, Toshiyuki; Arima, Chinatsu; Sato, Takahiko; Mitsudomi, Tetsuya; Yatabe, Yasushi; Takahashi, Takashi

doi:10.1158/0008-5472.can-08-3403

Cited by 35 publications

(19 citation statements)

References 37 publications

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“…We tested this hypothesis and confirmed that the mutant NRF2 signature is indeed a prognostic factor in SCC of the head and neck region and probably that of the lung. Interestingly, an independent study focusing on the prognostic molecular pathway in lung adenocarcinoma has identified the Peng_Rap_DN pathway, a top-ranking gene set enriched in mutant NRF2 clones, as a signature that is significantly associated with poor prognosis (46). This also supports our contention that the mutant NRF2 signature is a marker of poor prognosis.…”

Section: Discussionsupporting

confidence: 81%

Global Downstream Pathway Analysis Reveals a Dependence of Oncogenic NF-E2–Related Factor 2 Mutation on the mTOR Growth Signaling Pathway

et al. 2010

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In multicellular organisms, adaptive responses to oxidative stress are regulated by NF-E2-related factor 2 (NRF2), a master transcription factor of antioxidant genes and phase II detoxifying enzymes. Aberrant activation of NRF2 by either loss-of-function mutations in the Keap1 gene or gain-of-function mutations in the Nrf2 gene occurs in a wide range of human cancers, but details of the biological consequences of NRF2 activation in the cancer cells remain unclear. Here, we report that mutant NRF2 induces epithelial cell proliferation, anchorage-independent growth, and tumorigenicity and metastasis in vivo. Genome-wide gene expression profiling revealed that mutant NRF2 affects diverse molecular pathways including the mammalian target of rapamycin (mTOR) pathway. Mutant NRF2 upregulates RagD, a small G-protein activator of the mTOR pathway, which was also overexpressed in primary lung cancer. Consistently, Nrf2-mutated lung cancer cells were sensitive to mTOR pathway inhibitors (rapamycin and NVP-BEZ235) in both in vitro and an in vivo xenograft model. The gene expression signature associated with mutant NRF2 was a marker of poor prognosis in patients with carcinoma of the head and neck region and lung. These results show that oncogenic Nrf2 mutation induces dependence on the mTOR pathway during carcinogenesis. Our findings offer a rationale to target NRF2 as an anticancer strategy, and they suggest NRF2 activation as a novel biomarker for personalized molecular therapies or prognostic assessment. Cancer Res; 70(22); 9095-105. ©2010 AACR.

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Section: Discussionsupporting

confidence: 81%

Global Downstream Pathway Analysis Reveals a Dependence of Oncogenic NF-E2–Related Factor 2 Mutation on the mTOR Growth Signaling Pathway

et al. 2010

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“…The validation analyses also showed the heterogeneity of tumors across data sets and possibly across regions of the World. For example, in our set of North American AD, mTOR was not found to be an important predictor of survival (due to a high correlation with pathways that were not selected out of the model), but in both validation sets higher expression of the mTOR pathway was associated with poorer outcome which is consistent with previous reports [15]. Also, increased cell proliferation and a larger solid component was highly significant in both the North American and the Japanese lung cohorts, although not in the mostly stage 1 French cohort.…”

Section: Discussionsupporting

confidence: 90%

Clinically Relevant Characterization of Lung Adenocarcinoma Subtypes Based on Cellular Pathways: An International Validation Study

et al. 2010

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Lung adenocarcinoma (AD) represents a predominant type of lung cancer demonstrating significant morphologic and molecular heterogeneity. We sought to understand this heterogeneity by utilizing gene expression analyses of 432 AD samples and examining associations between 27 known cancer-related pathways and the AD subtype, clinical characteristics and patient survival. Unsupervised clustering of AD and gene expression enrichment analysis reveals that cell proliferation is the most important pathway separating tumors into subgroups. Further, AD with increased cell proliferation demonstrate significantly poorer outcome and an increased solid AD subtype component. Additionally, we find that tumors with any solid component have decreased survival as compared to tumors without a solid component. These results lead to the potential to use a relatively simple pathological examination of a tumor in order to determine its aggressiveness and the patient's prognosis. Additional results suggest the ability to use a similar approach to determine a patient's sensitivity to targeted treatment. We then demonstrated the consistency of these findings using two independent AD cohorts from Asia (N = 87) and Europe (N = 89) using the identical analytic procedures.

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“…Rapamycin in complex with FKBP12 interacts with mTOR and inhibits its activity in the mTORC1 complex (26). mTOR activity is increased in many tumors, including lung cancer (27); inhibition of mTOR function through rapamycin analogues is considered as promising therapeutic strategy. Earlier reports have suggested that activation of mTOR is a Smad-independent TGF-β pathway that regulates protein synthesis, complementing the Smad-mediated transcriptional regulation (28).…”

Section: Discussionmentioning

confidence: 99%

Identifying Inhibitors of Epithelial-Mesenchymal Transition by Connectivity Map–Based Systems Approach

Reka

Kuick

Kurapati

et al. 2011

Journal of Thoracic Oncology

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Background Acquisition of mesenchymal phenotype by epithelial cells by means of epithelial mesenchymal transition (EMT) is considered as an early event in the multi-step process of tumor metastasis. Therefore, inhibition of EMT might be a rational strategy to prevent metastasis. Methods Utilizing the global gene expression profile from a cell culture model of TGF-β-induced EMT, we identified potential EMT inhibitors. We used a publicly available database (www.broad.mit.edu/cmap) comprising gene expression profiles obtained from multiple different cell lines in response to various drugs to derive negative correlations to EMT gene expression profile using Connectivity Map (C-Map), a pattern matching tool. Results Experimental validation of the identified compounds showed rapamycin as a novel inhibitor of TGF-β signaling along with 17-AAG, a known modulator of TGF-β pathway. Both of these compounds completely blocked EMT and the associated migratory and invasive phenotype. The other identified compound, LY294002, demonstrated a selective inhibition of mesenchymal markers, cell migration and invasion, without affecting the loss of E-cadherin expression or Smad phosphorylation. Conclusions Collectively, our data reveals that rapamycin is a novel modulator of TGF-β signaling, and along with 17-AAG and LY294002, could be used as therapeutic agent for inhibiting EMT. Also, this analysis demonstrates the potential of a systems approach in identifying novel modulators of a complex biological process.

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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

Cited by 35 publications

References 37 publications

Global Downstream Pathway Analysis Reveals a Dependence of Oncogenic NF-E2–Related Factor 2 Mutation on the mTOR Growth Signaling Pathway

Global Downstream Pathway Analysis Reveals a Dependence of Oncogenic NF-E2–Related Factor 2 Mutation on the mTOR Growth Signaling Pathway

Clinically Relevant Characterization of Lung Adenocarcinoma Subtypes Based on Cellular Pathways: An International Validation Study

Identifying Inhibitors of Epithelial-Mesenchymal Transition by Connectivity Map–Based Systems Approach

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