Radiosensitization of NSCLC cells by EGFR inhibition is the result of an enhanced p53-dependent G1 arrest

• Published in: Radiotherapy and oncology Vol. 115; no. 1; pp. 120 - 127
• Main Authors: Kriegs, Malte, Gurtner, Kristin, Can, Yildiz, Brammer, Ingo, Rieckmann, Thorsten, Oertel, Reinhard, Wysocki, Marek, Dorniok, Franziska, Gal, Andreas, Grob, Tobias J, Laban, Simon, Kasten-Pisula, Ulla, Petersen, Cordula, Baumann, Michael, Krause, Mechthild, Dikomey, Ekkehard
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01-04-2015
• Subjects: Animals; Antibodies, Monoclonal, Humanized - pharmacology; Antineoplastic Agents - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - radiotherapy; Cell cycle; Cell Division; Cell Line, Tumor; Cetuximab; EGFR inhibition; Erlotinib Hydrochloride; G1 arrest; G1 Phase Cell Cycle Checkpoints - drug effects; G1 Phase Cell Cycle Checkpoints - radiation effects; Hematology, Oncology and Palliative Medicine; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Lung Neoplasms - radiotherapy; Mice; Mice, Nude; NSCLC; p53; Quinazolines - pharmacology; Radiation Tolerance - genetics; Radiosensitization; Receptor, Epidermal Growth Factor - antagonists & inhibitors; RNA, Small Interfering - genetics; Signal Transduction - drug effects; Signal Transduction - radiation effects; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays; EGFR inhibition; Radiosensitization; NSCLC; G1 arrest; Cell cycle; p53
• ISSN: 0167-8140; 1879-0887
• DOI: 10.1016/j.radonc.2015.02.018

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.