title: EGFRvIII-mediated radioresistance through a strong cytoprotective response.
abstract: The constitutively active, truncated epidermal growth factor receptor EGFRvIII lacks the ability of EGF binding due to a deletion of the NH(2)-terminal domain. EGFRvIII confers increased tumorigenicity, is coexpressed with EGFR wild type (wt) in human carcinoma and malignant glioma cells when grown as xenografts, but is not expressed in vitro. The effects of EGFRvIII expression on cellular radiation responses were studied in Chinese hamster ovary (CHO) cells transfected with plasmids expressing EGFRvIII (CHO.EGFRvIII) or EGFRwt (CHO.EGFRwt). CHO cells expressing similar levels of either receptor were employed to define their roles in response to EGF and ionizing radiation. EGF activated EGFRwt with no effect on EGFRvIII. In contrast, a single radiation exposure of 2 Gy resulted in a 2.8- and 4.3-fold increase in Tyr phosphorylation of EGFRwt and EGFRvIII, respectively. Downstream consequences of this radiation-induced activation were examined by inhibiting EGFRwt and EGFRvIII with AG1478 (kinase inhibitor). The radiation-induced 8.5-fold activation of the pro-proliferative mitogen-activated protein kinase and the 3.2-fold stimulation of the antiapoptotic AKT/phosphatidylinositol-3-kinase pathways by EGFRvIII far exceeded that in CHO.EGFR wt cells. Thus, based on colony formation and apoptosis assays, EGFRvIII expression conferred a stronger cytoprotective response to radiation than EGFRwt, resulting in relative radioresistance. Therefore, disabling EGFRvIII in addition to EGFRwt needs to be considered in any therapeutic approach aimed at targeting EGFR for tumor cell radiosensitization.
authors.affiliation: Department of Radiation Oncology, Heinrich-Heine University, Duesseldorf, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Lammering
authors.forename: Theodore H
authors.initials: TH
authors.lastname: Hewit
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Valerie
authors.forename: Joseph N
authors.initials: JN
authors.lastname: Contessa
authors.forename: George P
authors.initials: GP
authors.lastname: Amorino
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: Rupert K
authors.initials: RK
authors.lastname: Schmidt-Ullrich
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D016466:CHO Cells; D006224:Cricetinae; D019610:Cytoprotection; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D011836:Radiation Tolerance; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D020032:Tyrphostins; C410723:epidermal growth factor receptor VIII; C101044:RTKI cpd; C494918:AKT1 protein, human