oncogenic egfr signaling activates an mtorc2 nf κb pathway that promotes chemotherapy resistance

• DOI: 10.17615/dbv2-aa25
• Publication Date: 2011-11-01
• Authors: Tanaka K; Babic I; Nathanson D; Akhavan D; Guo D; GINI, Beatrice; Dang J; Zhu S; Yang H; De Jesus J; Amzajerdi AN; Zhang Y; Dibble CC; Dan H; Rinkenbaugh A; Yong WH; Vinters HV; Gera JF; Cavenee WK; Cloughesy TF; Manning BD; Baldwin AS; Mischel PS
• Keywords: 0301 basic medicine; 0303 health sciences; Brain Neoplasms; Cell Survival; TOR Serine-Threonine Kinases; NF-kappa B; PTEN Phosphohydrolase; chemotherapy resistance; mTORC2 kinase activity; epidermal growth factor receptor; 3. Good health; ErbB Receptors; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Drug Resistance, Neoplasm; Cell Line, Tumor; Humans; Cisplatin; Glioblastoma; Proto-Oncogene Proteins c-akt; Signal Transduction

Abstract Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models, and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), the most common malignant primary brain tumor of adults. We show that the common activating epidermal growth factor receptor (EGFR) mutation (EGFRvIII) stimulates mTORC2 kinase activity, which is partially suppressed by PTEN. mTORC2 signaling promotes GBM growth and survival and activates NF-κB. Importantly, this mTORC2–NF-κB pathway renders GBM cells and tumors resistant to chemotherapy in a manner independent of Akt. These results highlight the critical role of mTORC2 in the pathogenesis of GBM, including through the activation of NF-κB downstream of mutant EGFR, leading to a previously unrecognized function in cancer chemotherapy resistance. These findings suggest that therapeutic strategies targeting mTORC2, alone or in combination with chemotherapy, will be effective in the treatment of cancer. Significance: This study demonstrates that EGFRvIII-activated mTORC2 signaling promotes GBM proliferation, survival, and chemotherapy resistance through Akt-independent activation of NF-κB. These results highlight the role of mTORC2 as an integrator of two canonical signaling networks that are commonly altered in cancer, EGFR/phosphoinositide-3 kinase (PI3K) and NF-κB. These results also validate the importance of mTORC2 as a cancer target and provide new insights into its role in mediating chemotherapy resistance, suggesting new treatment strategies. Cancer Discovery; 1(6); 524–38. ©2011 AACR. Read the Commentary on this article by Wick et al., p. 475 This article is highlighted in the In This Issue feature, p. 457