Radiosensitization of HNSCC cells by EGFR inhibition depends on the induction of cell cycle arrests
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Malte Kriegs1,*, Ulla Kasten-Pisula1,*, Britta Riepen1, Konstantin Hoffer1, Nina Struve1, Laura Myllynen1, Friederike Braig2, Mascha Binder2, Thorsten Rieckmann1,3, Reidar Grénman4, Cordula Petersen1, Ekkehard Dikomey1, Kai Rothkamm1
1Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg – Eppendorf, Hubertus Wald Tumorzentrum – University Cancer Center Hamburg, 20246 Hamburg, Germany
2Department of Oncology and Hematology, BMT with section Pneumology, University Medical Center Hamburg – Eppendorf, Hubertus Wald Tumorzentrum – University Cancer Center Hamburg, 20246 Hamburg, Germany
3Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Hamburg – Eppendorf, Hubertus Wald Tumorzentrum – University Cancer Center Hamburg, 20246 Hamburg, Germany
4Department of Otorhinolaryngology – Head and Neck Surgery, University of Turku and Turku University Hospital, 20521 Turku, Finland
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Malte Kriegs, email: email@example.com
Keywords: EGFR, HNSCC, targeting, radiosensitization, cell cycle
Received: October 19, 2015 Accepted: April 18, 2016 Published: May 04, 2016
The increase in cellular radiosensitivity by EGF receptor (EGFR) inhibition has been shown to be attributable to the induction of a G1-arrest in p53-proficient cells. Because EGFR targeting in combination with radiotherapy is used to treat head and neck squamous cell carcinomas (HNSCC) which are predominantly p53 mutated, we tested the effects of EGFR targeting on cellular radiosensitivity, proliferation, apoptosis, DNA repair and cell cycle control using a large panel of HNSCC cell lines. In these experiments EGFR targeting inhibited signal transduction, blocked proliferation and induced radiosensitization but only in some cell lines and only under normal (pre-plating) conditions. This sensitization was not associated with impaired DNA repair (53BP1 foci) or induction of apoptosis. However, it was associated with the induction of a lasting G2-arrest. Both, the radiosensitization and the G2-arrest were abrogated if the cells were re-stimulated (delayed plating) with actually no radiosensitization being detectable in any of the 14 tested cell lines. Therefore we conclude that EGFR targeting can induce a reversible G2 arrest in p53 deficient HNSCC cells, which does not consequently result in a robust cellular radiosensitization. Together with recent animal and clinical studies our data indicate that EGFR inhibition is no effective strategy to increase the radiosensitivity of HNSCC cells.
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