Radiosensitization of HNSCC cells by EGFR inhibition depends on the induction of cell cycle arrests

TY - JOUR

T1 - Radiosensitization of HNSCC cells by EGFR inhibition depends on the induction of cell cycle arrests

AU - Kriegs, Malte

AU - Kasten-Pisula, Ulla

AU - Riepen, Britta

AU - Hoffer, Konstantin

AU - Struve, Nina

AU - Myllynen, Laura

AU - Braig, Friederike

AU - Binder, Mascha

AU - Rieckmann, Thorsten

AU - Grénman, Reidar

AU - Petersen, Cordula

AU - Dikomey, Ekkehard

AU - Rothkamm, Kai

PY - 2016/7/19

Y1 - 2016/7/19

N2 - 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.

AB - 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.

U2 - 10.18632/oncotarget.9161

DO - 10.18632/oncotarget.9161

M3 - SCORING: Journal article

C2 - 27281611

VL - 7

SP - 45122

EP - 45133

JO - ONCOTARGET

JF - ONCOTARGET

SN - 1949-2553

IS - 29

ER -