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: 4.57). 09/2007; 6(22):2750-4. DOI: 10.4161/cc.6.22.4922
Source: PubMed


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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    • "Interestingly, in vitro models have suggested that GBM cells expressing EGFRvIII are resistant to small molecule tyrosine kinase inhibitors (109). EGFRvIII signals to a mTOR complex 2 induced mechanism (110), thereby differing from the EGFR-mTOR complex 1 signaling axis, which may contribute to such therapy resistance. "
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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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    • "TKs, which are major inducers in GBM, exhibit crosstalk. The c-Met receptor is strongly phosphorylated as a function of EGFRvIII receptor levels, suggesting the presence of crosstalk between c-Met and EGFRvIII signaling, although the intermediary molecule has yet to be elucidated [77]. Axl RTK also follows a similar phosphorylation response as a function of EGFRvIII levels [77]. "
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