{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T00:48:39Z","timestamp":1774658919704,"version":"3.50.1"},"reference-count":26,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T00:00:00Z","timestamp":1596412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Dr. Senckenberg Institute of Neurooncology is supported by the Dr. Senckenberg Foundation.","award":["see above"],"award-info":[{"award-number":["see above"]}]},{"name":"ALL and ID haves received funding from the Medical Faculty of the Goethe University Frankfurt (Frankfurt research funding, FFF) via the program &quot;Patenschaftsmodell\u201d and a fellowship in the program \u201cClinician Scientist\u201d by the Else Kr\u00f6ner-Fresenius-Stiftun","award":["see above"],"award-info":[{"award-number":["see above"]}]},{"name":"ALE has received a scholarship by the Adolf Gutknecht trust.","award":["see above"],"award-info":[{"award-number":["see above"]}]},{"name":"PSZ has also received funding from the Medical Faculty of the Goethe University Frankfurt (FFF) via the programs &quot;Patenschaftsmodell\u201d and \u201cNachwuchsforscher\u201d.","award":["see above"],"award-info":[{"award-number":["see above"]}]},{"name":"UH is supported by the Robert-Bosch Foundation, Stuttgart, Germany.","award":["see above"],"award-info":[{"award-number":["see above"]}]},{"name":"JPS has received funding by the German Research Foundation (DFG)","award":["DFG 2175\/1-1"],"award-info":[{"award-number":["DFG 2175\/1-1"]}]},{"name":"J.P.S. and M.W.R. have received funding by the State of Hessen within the LOEWE program.","award":["see above"],"award-info":[{"award-number":["see above"]}]},{"name":"MWR has received a fellowship from the University Cancer Center Frankfurt (UCT) as well as from the Medical Faculty of the Goethe University Frankfurt (FFF) via the programs &quot;Nachwuchsforscher\u201d and \u201cClinician Scientists\u201d.","award":["see above"],"award-info":[{"award-number":["see above"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: The epidermal growth factor receptor (EGFR) signaling pathway is genetically activated in approximately 50% of glioblastomas (GBs). Its inhibition has been explored clinically but produced disappointing results, potentially due to metabolic effects that protect GB cells against nutrient deprivation and hypoxia. Here, we hypothesized that EGFR activation could disable metabolic adaptation and define a GB cell population sensitive to starvation. Methods: Using genetically engineered GB cells to model different types of EGFR activation, we analyzed changes in metabolism and cell survival under conditions of the tumor microenvironment. Results: We found that expression of mutant EGFRvIII as well as EGF stimulation of EGFR-overexpressing cells impaired physiological adaptation to starvation and rendered cells sensitive to hypoxia-induced cell death. This was preceded by adenosine triphosphate (ATP) depletion and an increase in glycolysis. Furthermore, EGFRvIII mutant cells had higher levels of mitochondrial superoxides potentially due to decreased metabolic flux into the serine synthesis pathway which was associated with a decrease in the NADPH\/NADP+ ratio. Conclusions: The finding that EGFR activation renders GB cells susceptible to starvation could help to identify a subgroup of patients more likely to benefit from starvation-inducing therapies.<\/jats:p>","DOI":"10.3390\/cancers12082144","type":"journal-article","created":{"date-parts":[[2020,8,3]],"date-time":"2020-08-03T06:16:47Z","timestamp":1596435407000},"page":"2144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Activation of Epidermal Growth Factor Receptor Sensitizes Glioblastoma Cells to Hypoxia-Induced Cell Death"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7209-3694","authenticated-orcid":false,"given":"Anna-Luisa","family":"Luger","sequence":"first","affiliation":[{"name":"Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany"},{"name":"University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt\/Mainz, 60590 Frankfurt am Main, Germany"},{"name":"Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadja I.","family":"Lorenz","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany"},{"name":"University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt\/Mainz, 60590 Frankfurt am Main, Germany"},{"name":"Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans","family":"Urban","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany"},{"name":"University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt\/Mainz, 60590 Frankfurt am Main, Germany"},{"name":"Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iris","family":"Div\u00e9","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany"},{"name":"University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt\/Mainz, 60590 Frankfurt am Main, Germany"},{"name":"Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna L.","family":"Engel","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany"},{"name":"University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt\/Mainz, 60590 Frankfurt am Main, Germany"},{"name":"Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Strassheimer","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany"},{"name":"University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt\/Mainz, 60590 Frankfurt am Main, Germany"},{"name":"Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7337-2380","authenticated-orcid":false,"given":"Katja","family":"Dettmer","sequence":"additional","affiliation":[{"name":"Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pia S.","family":"Zeiner","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany"},{"name":"University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt\/Mainz, 60590 Frankfurt am Main, Germany"},{"name":"Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shabnam","family":"Shaid","sequence":"additional","affiliation":[{"name":"Department of Medicine, Hematology\/Oncology, University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Struve","sequence":"additional","affiliation":[{"name":"Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum-University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malte","family":"Kriegs","sequence":"additional","affiliation":[{"name":"Laboratory of Radiobiology and Experimental Radiation Oncology, Hubertus Wald Tumorzentrum-University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0823-9027","authenticated-orcid":false,"given":"Ute","family":"Hofmann","sequence":"additional","affiliation":[{"name":"Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and University of T\u00fcbingen, 70376 Stuttgart, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter J.","family":"Oefner","sequence":"additional","affiliation":[{"name":"Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick N.","family":"Harter","sequence":"additional","affiliation":[{"name":"University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt\/Mainz, 60590 Frankfurt am Main, Germany"},{"name":"Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"},{"name":"Institute of Neurology (Edinger Institute), Goethe University, 60590 Frankfurt, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joachim P.","family":"Steinbach","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany"},{"name":"University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt\/Mainz, 60590 Frankfurt am Main, Germany"},{"name":"Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1402-6290","authenticated-orcid":false,"given":"Michael W.","family":"Ronellenfitsch","sequence":"additional","affiliation":[{"name":"Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Goethe University, 60528 Frankfurt am Main, Germany"},{"name":"University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Frankfurt\/Mainz, 60590 Frankfurt am Main, Germany"},{"name":"Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Goethe University, 60596 Frankfurt am Main, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"iv1","DOI":"10.1093\/neuonc\/noy131","article-title":"CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011\u20132015","volume":"20","author":"Ostrom","year":"2018","journal-title":"Neuro-Oncology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1056\/NEJMoa043330","article-title":"Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma","volume":"352","author":"Stupp","year":"2005","journal-title":"N. 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