Malte Kriegs1, Kristin Gurtner2, Yildiz Can3, Ingo Brammer3, Thorsten Rieckmann3, Reinhard Oertel4, Marek Wysocki2, Franziska Dorniok2, Andreas Gal5, Tobias J Grob6, Simon Laban7, Ulla Kasten-Pisula3, Cordula Petersen3, Michael Baumann8, Mechthild Krause8, Ekkehard Dikomey3. 1. Laboratory of Radiobiology & Experimental Radiooncology, Germany. Electronic address: m.kriegs@uke.uni-hamburg.de. 2. Department of Radiation Oncology and OncoRay - National Center for Radiation Research in Oncology, Germany. 3. Laboratory of Radiobiology & Experimental Radiooncology, Germany. 4. Institute of Clinical Pharmacology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. 5. Department of Human Genetics, Germany. 6. Department of Pathology, Germany. 7. Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Hamburg - Eppendorf, Germany. 8. 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.
Abstract
PURPOSE: 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. MATERIALS AND 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. CONCLUSION: 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.
PURPOSE: 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. MATERIALS AND 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. CONCLUSION: 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: James A Bonner; Hoa Q Trummell; Andrew B Bonner; Christopher D Willey; Markus Bredel; Eddy S Yang Journal: BMC Cancer Date: 2015-10-12 Impact factor: 4.430