Integration of Gene Dosage and Gene Expression in Non-Small Cell Lung Cancer, Identification of HSP90 as Potential Target

Ohio State University, United States of America
PLoS ONE (Impact Factor: 3.23). 02/2008; 3(3):e0001722. DOI: 10.1371/journal.pone.0001722
Source: PubMed
ABSTRACT
Lung cancer causes approximately 1.2 million deaths per year worldwide, and non-small cell lung cancer (NSCLC) represents 85% of all lung cancers. Understanding the molecular events in non-small cell lung cancer (NSCLC) is essential to improve early diagnosis and treatment for this disease.
In an attempt to identify novel NSCLC related genes, we performed a genome-wide screening of chromosomal copy number changes affecting gene expression using microarray based comparative genomic hybridization and gene expression arrays on 32 radically resected tumor samples from stage I and II NSCLC patients. An integrative analysis tool was applied to determine whether chromosomal copy number affects gene expression. We identified a deletion on 14q32.2-33 as a common alteration in NSCLC (44%), which significantly influenced gene expression for HSP90, residing on 14q32. This deletion was correlated with better overall survival (P = 0.008), survival was also longer in patients whose tumors had low expression levels of HSP90. We extended the analysis to three independent validation sets of NSCLC patients, and confirmed low HSP90 expression to be related with longer overall survival (P = 0.003, P = 0.07 and P = 0.04). Furthermore, in vitro treatment with an HSP90 inhibitor had potent antiproliferative activity in NSCLC cell lines.
We suggest that targeting HSP90 will have clinical impact for NSCLC patients.
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    • "hold potential as potent anti-cancer targets, and the expression and activity of each is correlated with cancer [7,21222324. Our results here show the synergistic effect of combined treatment of NSCLC cells with FAK inhibitor and Hsp90 inhibitors on inhibiting the growth of lung cancer cells. "
    [Show abstract] [Hide abstract] ABSTRACT: Discovery of effective drug combinations is a promising strategy to improve patient survival. This study explores the impact of heat shock protein 90 (Hsp90) inhibition in combination with focal adhesion kinase (FAK) inhibitor on the growth of non-small cell lung cancer cells (NSCLC cells). Our data show that 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG), a well-studied Hsp90 inhibitor, synergized with FAK inhibitor, PF-573228, on the growth inhibition of NSCLC cells. This combination effect was confirmed using additional chemically distinct Hsp90 inhibitor, STA-9090, which is currently undergoing phase 3 clinical evaluation. Co-treatment of NSCLC cells with Hsp90 and FAK inhibitors significantly enhanced the inhibition on long-term colony formation compared to that with single agent. Inhibition of FAK exacerbated the G2 cell cycle arrest and annexin-V apoptotic staining induced by 17-AAG. Further mechanistic studies revealed that the combination of Hsp90 and FAK inhibitors reduced the activity of canonical proliferative and survival Akt-mTOR signaling, and increased pro-apoptotic caspase activation. Interestingly, FAK inhibition alone induced feedback activation of pro-survival Erk signaling, which was abrogated by co-treatment with Hsp90 inhibitors. Both Hsp90 and FAK inhibitors are undergoing clinical evaluation. Our studies suggest the tandem of Hsp90 and FAK inhibitors may provide an effective treatment option for NSCLC patients.
    Full-text · Article · Sep 2015
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    • "Remarkably, in a number of tumors the HSP90AA1 gene is homozygously deleted, suggesting that these tumors may have a reduced level of malignancy . This hypothesis is supported by a comparative genome-wide analysis of 206 gastric cancer patients that reported loss of HSP90AA1 is indeed associated with favorable outcomes after surgery alone (Buffart et al., 2012), and is in agreement with other studies reporting that the absence of Hsp90α in tumor biopsies may serve as a biomarker for positive clinical outcomes (Gallegos et al., 2008; Cheng et al., 2012). Biologically, Hsp90α differs from Hsp90β in that Hsp90α is presently understood to function as a secreted extracellular agent in wound healing and inflammation in addition to its intracellular roles. "
    [Show abstract] [Hide abstract] ABSTRACT: Heat shock protein 90α (Hsp90α), encoded by the HSP90AA1 gene, is the stress inducible isoform of the molecular chaperone Hsp90. Hsp90α is regulated differently and has different functions when compared to the constitutively expressed Hsp90β isoform, despite high amino acid sequence identity between the two proteins. These differences are likely due to variations in nucleotide sequence within non-coding regions, which allows for specific regulation through interaction with particular transcription factors, and to subtle changes in amino acid sequence that allow for unique post-translational modifications. This article will specifically focus on the expression, function and regulation of Hsp90α. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jun 2015 · Gene
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    • "It controls cell cycle progression by simulating G1/S transition and may result in loss of cell cycle arrest and uncontrolled tumor growth when dysfunction [77] . Other identified significant proteins such as AR, ESR1, SRC, FYN, YWHAQ, YWHAZ, and HSP90AA1 were also shown to involve in carcinogenesis [7, 10, 20, 24, 39, 64, 70]. "
    [Show abstract] [Hide abstract] ABSTRACT: Lung cancerLung cancer is the leading cause of cancer deaths worldwide. Many studies have investigated the carcinogenic process and identified the biomarkers for signature classification. However, those biomarkers are mainly identified based only on analysis of genome-wide expression profiles, that is, the identification method cannot elucidate how the different genes in the biomarker gene set are related to each other. Therefore, from the systems perspective, we developed a network biomarkerNetwork biomarker construction scheme, which integrated microarray gene expression profiles and protein-protein interaction information, for molecular investigation and diagnosis of lung cancer. The network biomarkerNetwork biomarker consisted of two protein association networksProtein association network constructed for cancer samples and non-cancer samples. Based on the network biomarker, a total of 40 significant proteins were identified with carcinogenesis relevance values (CRVs) to gain insights into the lung carcinogenesis mechanism. In addition, the network biomarker was also acted as the diagnostic tool, demonstrated to be effective to diagnose the smokers with lung cancerLung cancer. Taken together, the network biomarker not only successfully sheds light on the mechanisms in lung carcinogenic process but also provides potential therapeutic targets to combat against cancer. © 2014 Springer Science+Business Media Dordrecht. All rights reserved.
    Full-text · Article · Mar 2014
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