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dc.contributor.authorNitta, Masayuki
dc.contributor.authorStommel, Jayne
dc.contributor.authorNg, Kimberly
dc.contributor.authorKesari, Santosh
dc.contributor.authorFurnari, Frank
dc.contributor.authorHoadley, Katherine A.
dc.contributor.authorCavenee, Webster K.
dc.contributor.authorKozono, David Eiichi
dc.contributor.authorKennedy, Richard
dc.contributor.authorZinn, Pascal Olivier
dc.contributor.authorKushwaha, Deepa S
dc.contributor.authorChin, Lynda
dc.contributor.authorDePinho, Ronald A.
dc.contributor.authorD'Andrea, Alan David
dc.contributor.authorChen, Clark Chin-Chung
dc.date.accessioned2011-03-27T20:38:45Z
dc.date.issued2010
dc.identifier.citationNitta, 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.issn1932-6203en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:4774196
dc.description.abstractDespite 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.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi:10.1371/journal.pone.0010767en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879424/pdf/en_US
dash.licenseLAA
dc.subjectgenetics and genomicsen_US
dc.subjectpharmacogenomicsen_US
dc.subjectmolecular biologyen_US
dc.subjectDNA repairen_US
dc.subjectoncologyen_US
dc.subjectneuro-oncologyen_US
dc.titleTargeting EGFR Induced Oxidative Stress by PARP1 Inhibition in Glioblastoma Therapyen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS ONEen_US
dash.depositing.authorKozono, David Eiichi
dc.date.available2011-03-27T20:38:45Z
dash.affiliation.otherHMS^Radiation Oncology-BWH-DFCI-CHen_US
dc.identifier.doi10.1371/journal.pone.0010767*
dash.authorsorderedfalse
dash.contributor.affiliatedChen, Clark Chin-Chung
dash.contributor.affiliatedZinn, Pascal Olivier
dash.contributor.affiliatedKushwaha, Deepa S
dash.contributor.affiliatedKozono, David
dash.contributor.affiliatedChin, Lynda
dash.contributor.affiliatedDePinho, Ronald A.
dash.contributor.affiliatedD'Andrea, Alan


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