Targeting EGFR Induced Oxidative Stress by PARP1 Inhibition in Glioblastoma Therapy
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Targeting EGFR Induced Oxidative Stress by PARP1 Inhibition in Glioblastoma Therapy
| Title: | Targeting EGFR Induced Oxidative Stress by PARP1 Inhibition in Glioblastoma Therapy |
| Author: |
Nitta, Masayuki; Stommel, Jayne; Ng, Kimberly; Kesari, Santosh; Furnari, Frank; Hoadley, Katherine A.; Cavenee, Webster K.; Kozono, David Eiichi; Kennedy, Richard; Zinn, Pascal Olivier; Kushwaha, Deepa S; Chin, Lynda; DePinho, Ronald A.; D'Andrea, Alan David; Chen, Clark Chin-Chung
Note: Order does not necessarily reflect citation order of authors. |
| Citation: | Nitta, Masayuki, David Kozono, Richard Kennedy, Jayne Stommel, Kimberly Ng, Pascal O. Zinn, Deepa Kushwaha, et al. 2010. Targeting EGFR induced oxidative stress by PARP1 inhibition in glioblastoma therapy. PLoS ONE 5(5): e10767. |
| Full Text & Related Files: |
2879424.pdf (712.9Kb; PDF) 
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| Abstract: | Despite the critical role of Epidermal Growth Factor Receptor (EGFR) in glioblastoma pathogenesis [1], [2], EGFR targeted therapies have achieved limited clinical efficacy [3]. Here we propose an alternate therapeutic strategy based on the conceptual framework of non-oncogene addiction [4], [5]. A directed RNAi screen revealed that glioblastoma cells over-expressing EGFRvIII [6], 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. |
| Published Version: | doi:10.1371/journal.pone.0010767 |
| Other Sources: | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879424/pdf/ |
| Terms of Use: | This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA |
| Citable link to this page: | http://nrs.harvard.edu/urn-3:HUL.InstRepos:4774196 |
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