Radiosensitization of HNSCC cells by EGFR inhibition depends on the induction of cell cycle arrests.
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.
Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.
Malte
M
Kriegs
Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.
Ulla
U
Kasten-Pisula
Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.
Britta
B
Riepen
Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.
Konstantin
K
Hoffer
Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.
Nina
N
Struve
Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.
Laura
L
Myllynen
Department of Oncology and Hematology, BMT with section Pneumology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.
Friederike
F
Braig
Department of Oncology and Hematology, BMT with section Pneumology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.
Mascha
M
Binder
Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.|Department of Otorhinolaryngology and Head and Neck Surgery, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.
Thorsten
T
Rieckmann
Department of Otorhinolaryngology - Head and Neck Surgery, University of Turku and Turku University Hospital, 20521 Turku, Finland.
Reidar
R
Grénman
Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.
Cordula
C
Petersen
Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.
Ekkehard
E
Dikomey
Laboratory of Radiobiology & Experimental Radiooncology, University Medical Center Hamburg - Eppendorf, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg, 20246 Hamburg, Germany.
Kai
K
Rothkamm
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology*; D006801:Humans; D011836:Radiation Tolerance / Q000187:drug effects*; D000077195:Squamous Cell Carcinoma of Head and Neck; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab
EGFR; HNSCC; cell cycle; radiosensitization; targeting