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

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          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.

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          Most cited references41

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          The role of autophagy in cancer development and response to therapy.

          Autophagy is a process in which subcellular membranes undergo dynamic morphological changes that lead to the degradation of cellular proteins and cytoplasmic organelles. This process is an important cellular response to stress or starvation. Many studies have shed light on the importance of autophagy in cancer, but it is still unclear whether autophagy suppresses tumorigenesis or provides cancer cells with a rescue mechanism under unfavourable conditions. What is the present state of our knowledge about the role of autophagy in cancer development, and in response to therapy? And how can the autophagic process be manipulated to improve anticancer therapeutics?
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            Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response.

            Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.
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              Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix.

              Experimental tumors contain a significant fraction of microregions that are chronically or transiently hypoxic. Experimental evidence showing that hypoxia (and subsequent reoxygenation) may have a profound impact on malignant progression and on responsiveness to therapy is growing. The clinical relevance of tumor oxygenation in human solid malignancies is under investigation. We have developed and validated a clinically applicable method for measurement of tumor oxygenation in locally advanced cancer of the uterine cervix using a computerized polarographic electrode system. Applying this procedure in patients with cervical cancers
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                Author and article information

                Journal
                Autophagy
                Autophagy
                KAUP
                kaup20
                Autophagy
                Taylor & Francis
                1554-8627
                1554-8635
                2018
                29 January 2018
                29 January 2018
                : 14
                : 2
                : 283-295
                Affiliations
                [a ]Department of Radiotherapy, GROW – School for Oncology and Developmental Biology, Maastricht University Medical Centre+ , Maastricht, The Netherlands
                [b ]Department of Clincial Pathology, Zuyderland MC , Sittard-Geleen, The Netherlands
                [c ]Department of Neurosurgery, Maastricht University Medical Centre
                [d ]Department of Radiation Oncology, Radboud University Medical Center , Nijmegen, The Netherlands
                [e ]Neuroimmunology and Neuro-Oncology Unit, National Institute of Neurology and Neurosurgery , Mexico City, Mexico
                [f ]Heinrich- Heine University Duesseldorf , Germany
                [g ]Department of Radiation Oncology (MAASTRO Clinic), GROW School for Oncology and Developmental Biology , Maastricht University Medical Centre+, The Netherlands
                Author notes
                Kasper M. A. Rouschop Kasper.Rouschop@ 123456maastrichtuniversity.nl Maastricht Radiation Oncology (MaastRO) lab, GROW – School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands

                Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/kaup.

                Supplemental data for this article can be accessed here https://doi.org/10.1080/15548627.2017.1409926.

                Author information
                http://orcid.org/0000-0002-8887-4137
                http://orcid.org/0000-0002-4208-5415
                Article
                1409926
                10.1080/15548627.2017.1409926
                5902239
                29377763
                048f73ae-6a68-4aae-9537-f9a5a631f484
                © 2018 Taylor & Francis

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 18 January 2017
                : 2 November 2017
                : 21 November 2017
                Page count
                Figures: 6, Tables: 2, References: 55, Pages: 13
                Funding
                Funded by: Worldwide Cancer Research 10.13039/100011713
                Award ID: 16-0265
                Funded by: KWF Kankerbestrijding 10.13039/501100004622
                Award ID: 2012-5506, 2015-7735
                This work was supported by the Worldwide Cancer Research [grant number 16-0265]; STOPbraintumors.nl/rare diseases fund; KWF Kankerbestrijding [grant number 2012-5506], [grant number 2015-7735].
                Categories
                Research Papers - Basic Science
                Research Paper-Translational

                Molecular biology
                autophagy,chloroquine,egfr,egfrviii,glioblastoma,hypoxia,metabolic stress radiotherapy,starvation

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