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Published on: October 11, 2017
Targeting EGFR induced oxidative stress by PARP1 inhibition in glioblastoma therapy
Masayuki Nitta1, David Kozono, Richard Kennedy
1Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
Abstract:
Despite the critical role of Epidermal Growth Factor Receptor (EGFR) in glioblastoma pathogenesis, EGFR targeted therapies have achieved limited clinical efficacy. Here we propose an alternate therapeutic strategy based on the conceptual framework of non-oncogene addiction. A directed RNAi screen revealed that glioblastoma cells over-expressing EGFRvIII, an oncogenic variant of EGFR, become hyper-dependent on a variety of DNA repair genes. Among these, there was an enrichment of Base Excision Repair (BER) genes required for the repair of Reactive Oxygen Species (ROS)-induced DNA damage, including poly-ADP ribose polymerase 1 (PARP1). Subsequent studies revealed that EGFRvIII over-expression in glioblastoma cells caused increased levels of ROS, DNA strand break accumulation, and genome instability. In a panel of primary glioblastoma lines, sensitivity to PARP1 inhibition correlated with the levels of EGFR activation and oxidative stress. Gene expression analysis indicated that reduced expression of BER genes in glioblastomas with high EGFR expression correlated with improved patient survival. These observations suggest that oxidative stress secondary to EGFR hyper-activation necessitates increased cellular reliance on PARP1 mediated BER, and offer critical insights into clinical trial design.
Insights
Glioblastoma cells with EGFRvIII mutations depend on DNA repair genes like PARP1. Inhibiting PARP1 shows promise for treating these aggressive brain tumors by targeting their DNA repair mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal Growth Factor Receptor (EGFR) plays a key role in glioblastoma (GBM) development.
- EGFR-targeted therapies have shown limited success in treating GBM.
- Non-oncogene addiction is a potential therapeutic strategy for cancers.
Purpose of the Study:
- To explore a novel therapeutic strategy for glioblastoma targeting non-oncogene addiction.
- To investigate the role of DNA repair pathways in glioblastoma cells overexpressing EGFRvIII.
- To assess the therapeutic potential of inhibiting DNA repair genes, specifically PARP1, in EGFRvIII-driven glioblastoma.
Main Methods:
- A directed RNA interference (RNAi) screen was employed to identify genes crucial for glioblastoma cell survival.
- Analysis of DNA repair gene expression, including Base Excision Repair (BER) genes.
- Assessment of Reactive Oxygen Species (ROS) levels and DNA strand breaks.
- Evaluation of glioblastoma cell sensitivity to PARP1 inhibition.
- Gene expression analysis in patient samples correlating EGFR expression with BER gene levels and survival.
Main Results:
- Glioblastoma cells overexpressing EGFRvIII exhibit increased dependency on DNA repair genes, particularly those involved in Base Excision Repair (BER).
- EGFRvIII overexpression leads to elevated ROS levels, DNA strand breaks, and genomic instability.
- Sensitivity to PARP1 inhibition correlates with EGFR activation and oxidative stress levels in glioblastoma.
- Reduced expression of BER genes in high-EGFR glioblastomas is associated with improved patient survival.
Conclusions:
- EGFR hyper-activation in glioblastoma induces oxidative stress, creating a dependency on PARP1-mediated DNA repair.
- Targeting PARP1 represents a promising therapeutic strategy for glioblastomas driven by EGFR activation.
- These findings provide insights for designing future clinical trials for glioblastoma treatment.
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