Synergistic Blockade of EGFR and HER2 by New Generation EGFR Tyrosine Kinase Inhibitor Enhances Radiation Effect in Bladder Cancer Cells
Menée sur des lignées cellulaires de cancer humain de la vessie et à l'aide de xénogreffes sur des modèles murins, cette étude montre que l'inhibition conjointe des récepteurs EGFR et HER2 par l'erlotinib ou l'afatinib augmente l'effet de la radiothérapie sur les cellules tumorales
Blockade of epidermal growth factor receptor (EGFR) has been proved useful in enhancing the effect of radiotherapy, but the advantages of new generation EGFR tyrosine kinase inhibitors in radiosensitization are not well known. We used two human bladder cancer cells with wild-type EGFR and HER2 to study the synergism between irradiation and afatinib (an EGFR/HER2 dual kinase inhibitor) or erlotinib (an EGFR kinase inhibitor). Here, we showed that afatinib has better radiosensitizing effect than erlotinib in increasing cancer cell killing, percentage of apoptotic cells and DNA damage. Afatinib is also superior to erlotinib in combining radiation to decrease tumor size, inhibit glucose metabolism, and enhance apoptotic proteins in vivo. Finally, erlotinib suppressed cell growth and induced more DNA damage in bladder cancer cells transfected with HER2 shRNA but not in control vector-treated cells. In conclusion, concomitant blockade of radiation-activated EGFR and HER2 signaling by a new generation EGFR tyrosine kinase inhibitor better inhibits the growth of bladder cancer cells both in vitro and in vivo. The absence of radiosensitization by EGFR or HER2 inhibition alone and the greater radiosensitizing effect of EGFR inhibitor in HER2 knocked-down cells suggests the synergism between HER2 and EGFR in determining radiosensitivity. The regained radiosensitizing activity of erlotinib implies that with proper HER2 inhibition, EGFR tyrosine kinase is still a potential target to enhance radiotherapy effect in these seemingly unresponsive bladder cancer cells.
http://mct.aacrjournals.org/content/early/2015/01/14/1535-7163.MCT-13-0951.abstract 2015