Targeting EGFR Induced Oxidative Stress by PARP1 Inhibition in Glioblastoma Therapy

Masayuki Nitta, David Kozono, Richard Kennedy, Jayne Stommel, Kimberly Ng, Pascal O. Zinn, Deepa Kushwaha, Santosh Kesari, Frank Furnari, Katherine A. Hoadley, Lynda Chin, Ronald A. DePinho, Webster K. Cavenee, Alan D'Andrea, Clark C. Chen, Richard Kennedy

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56 Citations (Scopus)


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 overexpressing 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 overexpression 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 hyperactivation necessitates increased cellular reliance on PARP1 mediated BER, and offer critical insights into clinical trial design.

Original languageEnglish
Article numbere10767
Pages (from-to)-
Number of pages12
JournalPLoS ONE
Issue number5
Publication statusPublished - 24 May 2010


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