Targeting EGFR Induced Oxidative Stress by PARP1 Inhibition in Glioblastoma Therapy

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.

Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells

“…43 In addition, a link between EGFR hyperactivation, a common event in GBM, and increased ROS that creates a reliance on PARP1 has been reported. 45 However, the direct mechanism leading to increased ROS in GICs is still an open area of investigation as is the overall metabolic requirements for GICs. Nonetheless, our data indicated a higher level of oxidative base lesions and BrDU foci (ssDNA) in the GICs that were likely the direct result of ROS-induced damage.…”

Targeting DNA Repair Mechanisms to Treat Glioblastoma

“…Clinical trials have utilized PARP inhibitors in two ways: in combination with DNA damaging therapies and as a single agent for tumors deficient in homologous repair (e.g., BRCA1/2 mutated breast cancers) [87]. Further, epidermal growth factor receptor (EGFR) status may act as a predictive biomarker for PARP inhibition sensitivity [89]. The EGFR gene is overexpressed in ~50% of GBMs [90].…”

Key Principles in Glioblastoma Therapy

“…Our laboratory has demonstrated that EGFR hyperactivation results in increased accumulation of reactive oxygen species (ROS), which in turn cause cytotoxic DNA damage. To compensate for the deleterious effect of ROS, EGFR hyperactive glioblastomas exhibit increased reliance on DNA repair process that repair ROS related DNA damage 29 . Selective targeting of EGFR hyperactive glioblastomas can, thus, be achieved by inhibition of these repair process.…”

“…It is important to note that effects of therapies designed based on the principles of "oncogene addiction" and of "non-oncogene addiction" are inherently antagonistic. For instance, EGFR inhibition leads to a reduction of ROS, obviating the need for DNA repair 29 . In this context, combination of DNA repair inhibition and EGFR inhibition would not be desirable.…”