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

Abstract

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.

Receptor tyrosine kinase MET as potential target of multi‐kinase inhibitor and radiosensitizer sorafenib in HNSCC

“…The effects of sorafenib on MET and EGFR phosphorylation (Figure A) as well as the effect on cell survival with and without X‐irradiation (Figure B,C and Supporting Information Figure S1B) were confirmed using SAS as a second responder line . Although a reasonable block of HNSCC proliferation can be induced by EGFR inhibition, only minor cell inactivation and no efficient radiosensitization can be achieved as described recently . Therefore, EGFR inhibition is probably not the cause for sorafenib‐mediated cytotoxicity or radiosensitization, arguing for MET inhibition as the potential cause of sorafenib‐mediated cellular effects.…”

Dual blockade of PI3K and MEK in combination with radiation in head and neck cancer

“…PI3K/AKT/MTOR pathway sensitized endometrial cells to PARP inhibitors [46] . Conversely, inhibition of the EGFR signaling pathway has previously been shown not to induce radiosensitization in the cell lines used in the study [47] . The UT-SCC-15 cell line and xenograft is more radioresistant than UT-SCC-14 [48] .…”

G2-checkpoint targeting and radiosensitization of HPV/p16-positive HNSCC cells through the inhibition of Chk1 and Wee1

“…However, in HPV(À) cell lines we recently observed a similar phenomenon. Radiosensitization upon EGFR-inhibition was only evident in preplating assays and was largely restricted to p53-positive tumor cells [21,22]. We could show that the reason for radiosensitization conferred by EGFR inhibition in preplating assays was the induction of a long-term G1 and, in case of the only p53-deficient responder, G2-arrest in addition to the cell cycle arrests induced by radiation alone.…”