title: Oncogenic EGFR signaling activates an mTORC2-NF-κB pathway that promotes chemotherapy resistance.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USA.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Ivan
authors.initials: I
authors.lastname: Babic
authors.forename: David
authors.initials: D
authors.lastname: Nathanson
authors.forename: David
authors.initials: D
authors.lastname: Akhavan
authors.forename: Deliang
authors.initials: D
authors.lastname: Guo
authors.forename: Beatrice
authors.initials: B
authors.lastname: Gini
authors.forename: Julie
authors.initials: J
authors.lastname: Dang
authors.forename: Shaojun
authors.initials: S
authors.lastname: Zhu
authors.forename: Huijun
authors.initials: H
authors.lastname: Yang
authors.forename: Jason
authors.initials: J
authors.lastname: De Jesus
authors.forename: Ali Nael
authors.initials: AN
authors.lastname: Amzajerdi
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Christian C
authors.initials: CC
authors.lastname: Dibble
authors.forename: Hancai
authors.initials: H
authors.lastname: Dan
authors.forename: Amanda
authors.initials: A
authors.lastname: Rinkenbaugh
authors.forename: William H
authors.initials: WH
authors.lastname: Yong
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Gera
authors.forename: Webster K
authors.initials: WK
authors.lastname: Cavenee
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Manning
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
authors.forename: Paul S
authors.initials: PS
authors.lastname: Mischel
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002945:Cisplatin; D066246:ErbB Receptors; D016328:NF-kappa B; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C410723:epidermal growth factor receptor VIII; C494929:PTEN protein, human