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.
Highlights
Cancer therapeutic development has largely been driven by the principle of ‘‘oncogene addiction’’ – that cancer cells require increased activity of selected oncogenes and tumor ablation can be achieved by inhibition of these oncogenes [7]
Given the mutually compensatory nature of many DNA repair pathways [12,13], we reasoned that hyper-dependency on any particular DNA repair process would be most evident when cellular capacity for repair is saturated by exogenously introduced DNA damage
We selected Ionizing Radiation (IR) as a means of introducing DNA damage since IR is universally utilized in glioblastoma treatment
Summary
Cancer therapeutic development has largely been driven by the principle of ‘‘oncogene addiction’’ – that cancer cells require increased activity of selected oncogenes and tumor ablation can be achieved by inhibition of these oncogenes [7]. While EGFR mutations or copy number alterations are found in nearly 50% of all glioblastomas [1,2], EGFR inhibition has yet to yield significant improvements in clinical outcome [3]. The ineffectiveness of such targeted therapy is explained in part by mutations in downstream signaling molecules [3] and redundant signaling from multiple co-activated receptor tyrosine kinases [8]. Tumor cells become hyper-dependent on processes required to compensate for these stressful conditions This phenomenon is termed ‘‘non-oncogene addiction’’ since the compensatory processes required for tumor survival are not oncogenic. As hyperactivation of several EGFR downstream effectors, including RAS and STAT3, elicits increased DNA damage accumulation [9,10,11], we tested whether the expression of a clinically pertinent EGFR oncogene, EGFRvIII [6], caused increased requirement for DNA repair as a form of non-oncogene addiction
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