EGFRvIII expression triggers a metabolic dependency and therapeutic vulnerability sensitive to autophagy inhibition

Barry Jutten, Tom G. Keulers, Hanneke J. M. Peeters, Marco B. E. Schaaf, Kim G. M. Savelkouls, Inge Compter, Ruud Clarijs, Olaf E. M. G. Schijns, Linda Ackermans, Onno P. M. Teernstra, Marijke I. Zonneveld, Resi M. E. Colaris, Ludwig Dubois, Marc A. Vooijs, Johan Bussink, Julio Sotelo, Jan Theys, Guido Lammering, Kasper M. A. Rouschop*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Web of Science)

Abstract

Expression of EGFRvIII is frequently observed in glioblastoma and is associated with increased cellular proliferation, enhanced tolerance to metabolic stresses, accelerated tumor growth, therapy resistance and poor prognosis. We observed that expression of EGFRvIII elevates the activation of macroautophagy/autophagy during starvation and hypoxia and explored the underlying mechanism and consequence. Autophagy was inhibited (genetically or pharmacologically) and its consequence for tolerance to metabolic stress and its therapeutic potential in (EGFRvIII(+)) glioblastoma was assessed in cellular systems, (patient derived) tumor xenopgrafts and glioblastoma patients. Autophagy inhibition abrogated the enhanced proliferation and survival advantage of EGFRvIII(+) cells during stress conditions, decreased tumor hypoxia and delayed tumor growth in EGFRvIII(+) tumors. These effects can be attributed to the supporting role of autophagy in meeting the high metabolic demand of EGFRvIII(+) cells. As hypoxic tumor cells greatly contribute to therapy resistance, autophagy inhibition revokes the radioresistant phenotype of EGFRvIII(+) tumors in (patient derived) xenograft tumors. In line with these findings, retrospective analysis of glioblastoma patients indicated that chloroquine treatment improves survival of all glioblastoma patients, but patients with EGFRvIII(+) glioblastoma benefited most. Our findings disclose the unique autophagy dependency of EGFRvIII(+) glioblastoma as a therapeutic opportunity. Chloroquine treatment may therefore be considered as an additional treatment strategy for glioblastoma patients and can reverse the worse prognosis of patients with EGFRvIII(+) glioblastoma.
Original languageEnglish
Pages (from-to)283-295
Number of pages13
JournalAutophagy
Volume14
Issue number2
DOIs
Publication statusPublished - 1 Jan 2018

Keywords

  • Autophagy
  • chloroquine
  • EGFR
  • EGFRvIII
  • glioblastoma
  • hypoxia
  • metabolic stress radiotherapy
  • starvation
  • GROWTH-FACTOR RECEPTOR
  • CONFERS ENHANCED TUMORIGENICITY
  • VARIANT-III CONTRIBUTES
  • GLIOBLASTOMA-MULTIFORME
  • RADIATION-THERAPY
  • HYPOXIA TOLERANCE
  • PROGNOSTIC VALUE
  • TUMOR HYPOXIA
  • CANCER
  • CELLS

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