title: Radiosensitization of NSCLC cells by EGFR inhibition is the result of an enhanced p53-dependent G1 arrest.
abstract: OBJECTIVE
  How EGF receptor (EGFR) inhibition induces cellular radiosensitization and with that increase in tumor control is still a matter of discussion. Since EGFR predominantly regulates cell cycle and proliferation, we studied whether a G1-arrest caused by EGFR inhibition may contribute to these effects.
  
  
  METHODS
  We analyzed human non-small cell lung cancer (NSCLC) cell lines either wild type (wt) or mutated in p53 (A549, H460, vs. H1299, H3122) and HCT116 cells (p21 wt and negative). EGFR was inhibited by BIBX1382BS, erlotinib or cetuximab; p21 was knocked down by siRNA. Functional endpoints analyzed were cell signaling, proliferation, G1-arrest, cell survival as well as tumor control using an A549 tumor model.
  
  
  RESULTS
  When combined with IR, EGFR inhibition enhances the radiation-induced permanent G1 arrest, though solely in cells with intact p53/p21 signaling. This increase in G1-arrest was always associated with enhanced cellular radiosensitivity. Strikingly, this effect was abrogated when cells were re-stimulated, suggesting the initiation of dormancy. In line with this, only a small non-significant increase in tumor control was observed for A549 tumors treated with fractionated RT and EGFR inhibition.
  
  
  CONCLUSIONS
  For NSCLC cells increase in radiosensitivity by EGFR inhibition results from enhanced G1-arrest. However, this effect does not lead to improved tumor control because cells can be released from this arrest by re-stimulation.
authors: Laboratory of Radiobiology & Experimental Radiooncology, Germany. Electronic address: m.kriegs@uke.uni-hamburg.de.
authors: Malte
authors: M
authors: Kriegs
authors: Department of Radiation Oncology and OncoRay - National Center for Radiation Research in Oncology, Germany.
authors: Kristin
authors: K
authors: Gurtner
authors: Laboratory of Radiobiology & Experimental Radiooncology, Germany.
authors: Yildiz
authors: Y
authors: Can
authors: Laboratory of Radiobiology & Experimental Radiooncology, Germany.
authors: Ingo
authors: I
authors: Brammer
authors: Laboratory of Radiobiology & Experimental Radiooncology, Germany.
authors: Thorsten
authors: T
authors: Rieckmann
authors: Institute of Clinical Pharmacology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
authors: Reinhard
authors: R
authors: Oertel
authors: Department of Radiation Oncology and OncoRay - National Center for Radiation Research in Oncology, Germany.
authors: Marek
authors: M
authors: Wysocki
authors: Department of Radiation Oncology and OncoRay - National Center for Radiation Research in Oncology, Germany.
authors: Franziska
authors: F
authors: Dorniok
authors: Department of Human Genetics, Germany.
authors: Andreas
authors: A
authors: Gal
authors: Department of Pathology, Germany.
authors: Tobias J
authors: TJ
authors: Grob
authors: Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Hamburg - Eppendorf, Germany.
authors: Simon
authors: S
authors: Laban
authors: Laboratory of Radiobiology & Experimental Radiooncology, Germany.
authors: Ulla
authors: U
authors: Kasten-Pisula
authors: Laboratory of Radiobiology & Experimental Radiooncology, Germany.
authors: Cordula
authors: C
authors: Petersen
authors: Department of Radiation Oncology and OncoRay - National Center for Radiation Research in Oncology, Germany; German Cancer Consortium (DKTK) Dresden, Germany; German Cancer Research Center (DKFZ) Heidelberg, Germany; Hemholtz-Zentrum Dresden - Rossendorf, Germany.
authors: Michael
authors: M
authors: Baumann
authors: Department of Radiation Oncology and OncoRay - National Center for Radiation Research in Oncology, Germany; German Cancer Consortium (DKTK) Dresden, Germany; German Cancer Research Center (DKFZ) Heidelberg, Germany; Hemholtz-Zentrum Dresden - Rossendorf, Germany.
authors: Mechthild
authors: M
authors: Krause
authors: Laboratory of Radiobiology & Experimental Radiooncology, Germany.
authors: Ekkehard
authors: E
authors: Dikomey
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D002455:Cell Division; D045744:Cell Line, Tumor; D000068818:Cetuximab; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011799:Quinazolines; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
keywords: Cell cycle; EGFR inhibition; G1 arrest; NSCLC; Radiosensitization; p53