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Uncovering therapeutic targets for glioblastoma: a systems biology approach
Paul H Huang1, Webster K Cavenee, Frank B Furnari
1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
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.
Insights
Glioblastoma treatment resistance may be overcome by targeting the EGFRvIII mutation. Systems biology revealed a novel crosstalk between EGFRvIII and c-Met, suggesting combination therapy for glioblastoma (GBM).
Area of Science:
- Oncology
- Molecular Biology
- Systems Biology
Background:
- Glioblastoma (GBM), WHO grade IV, remains a devastating adult cancer with limited treatment options.
- The mutated Epidermal Growth Factor Receptor variant III (EGFRvIII) is frequently found in GBM and associated with treatment resistance.
Purpose of the Study:
- To elucidate the molecular mechanisms by which EGFRvIII impacts GBM cell physiology.
- To identify novel therapeutic targets for glioblastoma by uncovering previously unknown signaling pathways.
Main Methods:
- Phosphoproteomic analysis was employed to map EGFRvIII signaling networks in GBM cells.
- Systems biology approaches, including data clustering, were used to identify signaling pathway crosstalk.
- In vitro cell viability assays were performed using combined EGFR and c-Met kinase inhibitors.
Main Results:
- Phosphoproteomic analysis provided insights into oncogene dose effects and differential pathway utilization in EGFRvIII-mutated GBM.
- A previously undescribed crosstalk between EGFRvIII and the c-Met receptor was identified.
- Combined inhibition of EGFR and c-Met kinases significantly reduced GBM cell viability in vitro.
Conclusions:
- Systems biology is a valuable tool for understanding glioblastoma tumor biology at a molecular level.
- The identified crosstalk between EGFRvIII and c-Met presents a promising, non-intuitive therapeutic strategy for GBM treatment.
- Targeting both EGFR and c-Met kinases simultaneously offers a potential approach to overcome treatment resistance in glioblastoma.
