Abstract 1119: Interplay between EGFRvIII and c-Met in glioblastoma multiforme

Abstract

Abstract Glioblastoma multiforme (GBM) is a highly invasive and lethal brain tumor which is associated with a high recurrence rate after surgery and an increased resistance to irradiation and chemotherapies. Consequently, patients suffering from GBM have a poor prognosis and a high mortality rate with an average life expectancy of less than 15 months. Key signaling components, especially receptor tyrosine kinases (RTKs), are aberrantly activated in GBM. The most frequent is the epidermal growth factor receptor (EGFR) and here the most commonly activated form, EGFRvIII, augments GBM invasiveness, promotes therapy resistance and connotes poor prognosis. There are five EGFR approved inhibitors and interestingly clinical studies have indicated that targeting the activity of the EGFR in association with conventional GBM therapies does little to inhibit tumor growth. The underlying mechanistic reasoning for this poor response are not understood and may reflect EGFR-induced trans-activation of other RTKs such as the hepatocyte growth factor receptor (c-Met), or uncoupling of EGFR signaling from its downstream mediators. Several studies have indicated that EGFR can trans-activate c-Met and consequently the dual targeting of both EGFR and c-Met significantly decreases the growth of EGFRvIII expressing tumor xenografts, indicating that inhibiting both EGFR and c-Met activity may prove beneficial in GBM therapy. Currently, the only known ligand for c-Met is the hepatocyte growth factor (HGF). Thus we hypothesize that EGFR induced HGF production is critical for the increased tumorgenicity observed in EGFRvIII expressing GBM cells. Using GBM cell lines we show that c-Met activation is increased in GBM cells that both stably and transiently express EGFRvIII. Furthermore, conditioned media taken from GBM cells expressing EGFRvIII can activate c-Met signaling in GBM cells that lack EGFRvIII. In both instances we see that the kinase activity of the EGFRvIII partially contributes to the production of HGF and the activation of c-Met in GBM cells. Aberrant c-Jun terminal kinase signaling (JNK) can be detected in the majority of patient GBMs. Using GBM cells stably lacking JNK2α2 we identify JNK2α2 signaling as a potential mechanism behind EGFRvIII activation of c-Met via the production of HGF in EGFRvIII GBM expressing cells. Taken together our data describes a novel role for JNK2α2 in mediating GBM tumorgenicity through the regulation of HGF production and the subsequent activation of c-Met signaling in GBM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1119. doi:10.1158/1538-7445.AM2011-1119