Abstract 5071: Defining the role of canonical MAPK signaling in glioma initiation and maintenance

Abstract

Abstract Mutations in receptor tyrosine kinase (RTK) growth factor receptors e.g., EGFR, PDGFR, MET and ERBB2 which result in constitutive downstream signaling of the canonical mitogen activated protein kinase (MAPK) (e.g., RAS/RAF/MEK/ERK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways, are found in almost all World Health Organization (WHO) grade II, III, and IV astrocytomas. KRAS, BRAF and CRAF mutations occur in approximately 6%, 72% and 2% of low grade gliomas (WHO Grade I), respectively. A recent study also found a 5-fold increase in RAF serine/threonine kinase activity in a significant series of grade III and IV gliomas, coupled with a 12-fold increase in BRAF and a 2-fold increase in CRAF protein levels. By using an established glioma mouse model, it has been demonstrated that KRas, CRAF or BRAF expression in nestin expressing neural progenitor cells, combined with either Akt activation or Ink4a/Arf loss, leads to the development of high grade gliomas. Together, these data clearly demonstrate the importance of MAPK signaling in glioma development. However, KRAS, BRAF and CRAF are all differently regulated. To further validate a role for canonical MAPK signaling in glioma formation, we have evaluated the effect of constitutive MEK1 activity in glioma formation in vitro and in vivo. While expression of activated MEK1 alone is not sufficient for tumorigenesis, the combination of activated MEK1 and Akt, or MEK1 with Ink4a/Arf loss leads to glioma formation. To assess the efficacy of targeting MAPK signaling in gliomas, we treated a large panel human GBM cell lines with the MEK inhibitor PD0325901 alone and in combination with the PI3K/mTOR inhibitor BEZ235. Cell lines with the highest levels of ERK activation were the most sensitive to MEK inhibition while those with the highest levels of AKT activation were protected from apoptosis following MAPK inhibition. Treatment with BEZ235, in combination with PD0325901, caused significantly higher levels of apoptosis in the glioma cell lines. Importantly, neither treatment induced apoptosis in normal human astrocytes. Our studies demonstrate that activation and signaling through the MAPK pathway following Ink4a/Arf loss or Akt activation can give rise to high grade gliomas; moreover MAPK inhibition, when combined with PI3K/mTOR inhibition may prove to be an effective treatment for gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5071.