Uncovering Therapeutic Targets FOR Glioblastoma: A Systems Biology Approach

Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Cell cycle (Georgetown, Tex.) (Impact Factor: 5.01). 09/2007; 6(22):2750-4. DOI: 10.4161/cc.6.22.4922
Source: PubMed

ABSTRACT Even though glioblastoma, WHO grade IV (GBM) is one of the most devastating adult cancers, current treatment regimens have not led to any improvements in patient life expectancy or quality of life. The constitutively active EGFRvIII receptor is one of the most commonly mutated proteins in GBM and has been linked to radiation and chemotherapeutic resistance. To define the mechanisms by which this protein alters cell physiology, we have recently performed a phosphoproteomic analysis of EGFRvIII signaling networks in GBM cells. The results of this study provided important insights into the biology of this mutated receptor, including oncogene dose effects and differential utilization of signaling pathways. Moreover, clustering of the phosphoproteomic data set revealed a previously undescribed crosstalk between EGFRvIII and the c-Met receptor. Treatment of the cells with a combination employing both EGFR and c-Met kinase inhibitors dramatically decreased cell viability in vitro. In this perspective, we highlight the use of systems biology as a tool to better understand the molecular basis of GBM tumor biology as well as to uncover non-intuitive candidates for therapeutic target validation.

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Available from: Paul H Huang, Aug 03, 2015
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    • "It has been shown that transactivation of c-Met by the epidermal growth factor receptor (EGFR) is an important contributing factor to aberrant c-Met signaling [17– 19] and depends on the direct association with active EGFR [20]. In GBMs, approximately 40% of tumors overexpressing wild-type EGFR coexpress a 2-to 7-exon deletion mutant of the EGFR, known as the ΔEGFR or EGFRvIII [21]. This cancer-specific mutant signals constitutively at a low level in a ligand-independent manner, owing to inefficient receptor dimerization [22] [23] [24], internalization, and down-regulation [25] [26]. "
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    ABSTRACT: The hepatocyte growth factor receptor (c-Met) and a constitutively active mutant of the epidermal growth factor receptor (ΔEGFR/EGFRvIII) are frequently overexpressed in glioblastoma (GBM) and promote tumorigenesis. The mechanisms underlying elevated hepatocyte growth factor (HGF) production in GBM are not understood. We found higher, coordinated mRNA expression levels of HGF and c-Met in mesenchymal (Mes) GBMs, a subtype associated with poor treatment response and shorter overall survival. In an HGF/c-Met-dependent GBM cell line, HGF expression declined upon silencing of c-Met using RNAi or by inhibiting its activity with SU11274. Silencing c-Met decreased anchorage-independent colony formation and increased the survival of mice bearing intracranial GBM xenografts. Consistent with these findings, c-Met activation by ΔEGFR also elevated HGF expression, and the inhibition of ΔEGFR with AG1478 reduced HGF levels. Interestingly, c-Met expression was required for ΔEGFR-mediated HGF production, anchorage-independent growth, and in vivo tumorigenicity, suggesting that these pathways are coupled. Using an unbiased mass spectrometry-based screen, we show that signal transducer and activator of transcription 3 (STAT3) Y705 is a downstream target of c-Met signaling. Suppression of STAT3 phosphorylation with WP1193 reduced HGF expression in ΔEGFR-expressing GBM cells, whereas constitutively active STAT3 partially rescued HGF expression and colony formation in c-Met knockdown cells expressing ΔEGFR. These results suggest that the c-Met/HGF signaling axis is enhanced by ΔEGFR through increased STAT3-dependent HGF expression and that targeting c-Met in Mes GBMs may be an important strategy for therapy.
    Neoplasia (New York, N.Y.) 01/2013; 15(1):73-84. · 5.40 Impact Factor
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    • "Glioblastoma U87MG EGFRvIII Radiation/Chemotherapy-Resistant Schmidt et al. 2002 Chakravarti et al. 2004 Huang et al. 2007 Non-Small Cell Lung Cancer H1650 delE746-A750 Tyrosine Kinase Inhibitor-Sensitive Lynch et al. 2004 Paez et al. 2004 Pao et al. 2004 Sordella et al. 2004 H1975 L858R+Y790M Tyrosine Kinase Inhibitor-Resistant "
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    ABSTRACT: Epidermal Growth Factor Receptor (EGFR) mutants are associated with resistance to chemotherapy, radiation, and targeted therapies. Here we found that the phytochemical 3,3'-Diindolylmethane (DIM) can inhibit the growth and also the invasion of breast cancer, glioma, and non-small cell lung cancer cells regardless of which EGFR mutant is expressed and the drug-resistant phenotype. DIM reduced an array of growth factor signaling pathways and altered cell cycle regulators and apoptotic proteins favoring cell cycle arrest and apoptosis. Therefore, DIM may be used in treatment regimens to inhibit cancer cell growth and invasion, and potentially overcome EGFR mutant-associated drug resistance.
    Cancer letters 03/2010; 295(1):59-68. DOI:10.1016/j.canlet.2010.02.014 · 5.62 Impact Factor
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    • "K E Y W O R D S EGFR EGFRvIII cancer heterodimerization endocytosis trafficking recycling lysosome THE NATURALLY OCCURRING EGFR mutant, with a deletion of aa 6–273 in the extracellular domain, designated EGFR variant III (EGFRvIII, delta EGFR, or de2-7 EGFR) is expressed in a number of cancers, most notably glioblastoma (Lorimer 2002; Huang et al. 2007a; Sonabend et al. 2007). This mutant does not bind EGF (Moscatello et al. 1996); nevertheless, it is constitutively autophosphorylated (Nishikawa et al. 1994; Fernandes et al. 2001) and is present at the cell membrane (Wikstrand et al. 1997) and suffers from impaired downregulation, which is a result of decreased association with Cbl proteins and subsequently decreased polyubiquitination and degradation (Huang et al. 1997; Schmidt et al. 2003; Han et al. 2006; Grandal et al. 2007). "
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    ABSTRACT: A constitutively active epidermal growth factor receptor (EGFR) mutant, EGFR variant III (EGFRvIII), has been detected at high frequencies in certain human cancers. This study evaluated transactivation and trafficking of erbB family members as a result of constitutive EGFR activity in a cancer cell line. Expression of EGFRvIII modulated erbB family members through different mechanisms; the erbB3 mRNA level was reduced, whereas wild-type EGFR (wtEGFR) and erbB2 protein levels were diminished, with no change in their mRNA levels, and there was no change in the erbB4 expression level. Both EGFR and erbB2 were internalized as a result of EGFRvIII's activity and redistributed to the cell surface upon addition of AG1478, an inhibitor of wtEGFR/EGFRvIII catalytic activity. Acute activation of EGFRvIII by removing AG1478 from cells increased phosphorylation of both wtEGFR and erbB2 and caused differential trafficking of EGFRvIII's activation partners; wtEGFR was directed primarily to lysosomal compartments and partially to recycling compartments, whereas erbB2 was directed primarily to recycling compartments and partially to lysosomal compartments. Our data demonstrate that the constitutive activity of EGFRvIII is sufficient to trigger endocytosis and trafficking of wtEGFR and erbB2, which may play a role in activating signaling pathways that are triggered during receptor endocytosis.
    Journal of Histochemistry and Cytochemistry 02/2010; 58(6):529-41. DOI:10.1369/jhc.2010.955104 · 2.40 Impact Factor
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