Abstract 1810: Analysis of EGFRvIII mediated responses driven by JNK2 in Glioblastoma Multiforme.
Authors: Saunders Vanessa , Fallahi-Sichani Mohammad , Ling Yuan Yuan , Duckett Derek 
Published: August 2014

The most malignant central nervous system cancer, Glioblastoma Mulitforme (GBM), accounts for the majority of primary brain cancer-related deaths (Porter, McCarthy et al. 2010) and has an average post-diagnostic survival rate of just over 14 months (Behin, Hoang-Xuan et al. 2003; Stupp, Mason et al. 2005; Louis, Ohgaki et al. 2007). The epidermal growth factor receptor (EGFR) (Wong, Ruppert et al. 1992; Mukasa, Wykosky et al. 2010) has been shown to play central roles in GBM tumorigenesis and therapeutic resistance and reports have indicated that ∼50% of all GBMs display aberrant activation of EGFR and of these ∼50% also express a ligand-independent, constitutively active mutant, EGFRvIII (Nishikawa, Ji et al. 1994) that is associated with increased tumorigenecity and mortality (Heimberger, Hlatky et al. 2005; Heimberger, Suki et al. 2005). In addition, several reports have indicated that the c-Jun N-terminal kinase 2 (JNK2) is activated in the majority of GBM tumors when compared to normal brain tissue (Antonyak, Kenyon et al. 2002; Tsuiki, Tnani et al. 2003; Cui, Han et al. 2006) and JNK2 activation strongly correlates with both GBM histological grade and expression of EGFR (Li, Wang et al. 2008). Current therapies specifically targeting the EGFR have limited success and the universal resurgence of tumors post-treatment occurs due to infiltrating tumor cells that escape initial surgery and exhibit profound resistance to irradiation and current chemotherapy treatments (Claes, Idema et al. 2007). Therefore, the identification of novel tractable targets for improved therapeutics and the molecular and genetic profiling of GBMs continues to be a necessity. To this end we have compared the gene expression profiles of U87 GBM cells with cells expressing EGFRvIII (U87EGFRvIII) and specifically studied genes modulated by JNK2 using microarray analysis comparing U87EGFRvIII cells expressing either short hairpin RNA directed against JNK2 (U87EGFRvIIIshJNK2) or a non-silencing control (U87EGFRvIIIshNS). Gene expression profiles revealed 390 EGFRvIII-induced genes that were significantly associated with targeted loss of JNK2 expression by a minimum of 2 fold on comparison to non-silencing controls. JNK2 modulated gene clusters related to cell movement were revealed with Ingenuity Pathway Analysis (IPA) and included interesting genes such as HGF, MMP7, FGF10, PDGFRA and IGFBP5. Ultimately, these studies, allowed us to further understand the molecular mechanisms driving EGFRvIII-induced tumorigenesis and such knowledge will ultimately enhance our ability to develop an efficacious GBM therapy that can increase the effectiveness of clinically approved drugs.

Citation Format: Vanessa Saunders, Mohammad Fallahi-Sichani, Yuan Yuan Ling, Derek Duckett. Analysis of EGFRvIII mediated responses driven by JNK2 in Glioblastoma Multiforme. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1810. doi:10.1158/1538-7445.AM2013-1810