Article

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
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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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    • "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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    • "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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    • "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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