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

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dc.contributor.author Nitta, Masayuki
dc.contributor.author Stommel, Jayne
dc.contributor.author Ng, Kimberly
dc.contributor.author Kesari, Santosh
dc.contributor.author Furnari, Frank
dc.contributor.author Hoadley, Katherine A.
dc.contributor.author Cavenee, Webster K.
dc.contributor.author Kozono, David Eiichi
dc.contributor.author Kennedy, Richard
dc.contributor.author Zinn, Pascal Olivier
dc.contributor.author Kushwaha, Deepa S
dc.contributor.author Chin, Lynda
dc.contributor.author DePinho, Ronald A.
dc.contributor.author D'Andrea, Alan David
dc.contributor.author Chen, Clark Chin-Chung
dc.date.accessioned 2011-03-27T20:38:45Z
dc.date.issued 2010
dc.identifier.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. en_US
dc.identifier.issn 1932-6203 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4774196
dc.description.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. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.pone.0010767 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879424/pdf/ en_US
dash.license LAA
dc.subject genetics and genomics en_US
dc.subject pharmacogenomics en_US
dc.subject molecular biology en_US
dc.subject DNA repair en_US
dc.subject oncology en_US
dc.subject neuro-oncology en_US
dc.title Targeting EGFR Induced Oxidative Stress by PARP1 Inhibition in Glioblastoma Therapy en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS ONE en_US
dash.depositing.author Kozono, David Eiichi
dc.date.available 2011-03-27T20:38:45Z
dash.affiliation.other HMS^Radiation Oncology-BWH-DFCI-CH en_US

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