Synergistic blockade of EGFR and HER2 by new-generation EGFR tyrosine kinase inhibitor enhances radiation effect in bladder cancer cells
Journal
Molecular Cancer Therapeutics
Journal Volume
14
Journal Issue
3
Pages
810-820
Date Issued
2015
Author(s)
Ho P.-Y.
KAI-YUAN TZEN
Tuan T.-F.
Liu W.-L.
Abstract
Blockade of EGFR has been proved useful in enhancing the effect of radiotherapy, but the advantages of new-generation EGFR tyrosine kinase inhibitors (TKI) in radiosensitization are not well known. We used two human bladder cancer cells with wild-type EGFR 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, the 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 TKI better inhibits the growth of bladder cancer cells both in vitro and in vivo. The absence of radiosensitization by EGFR inhibition alone and the greater radiosensitizing effect of EGFR inhibitor in HER2 knocked down cells suggest 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. ? 2015 American Association for Cancer Research.
SDGs
Other Subjects
afatinib; erlotinib; short hairpin RNA; afatinib; antineoplastic agent; EGFR protein, human; epidermal growth factor receptor; epidermal growth factor receptor 2; ERBB2 protein, human; erlotinib; protein kinase B; protein kinase inhibitor; quinazoline derivative; radiosensitizing agent; Article; bladder cancer; bladder cancer cell line; cell growth; cell killing; controlled study; DNA damage; down regulation; drug effect; glucose metabolism; human; human cell; in vitro study; in vivo study; male; mouse; nonhuman; priority journal; radiation response; radiosensitivity; radiosensitization; tumor volume; wild type; animal; antagonists and inhibitors; apoptosis; cell proliferation; drug effects; metabolism; nude mouse; radiation tolerance; signal transduction; tumor cell line; Urinary Bladder Neoplasms; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; DNA Damage; Erlotinib Hydrochloride; Humans; Male; Mice; Mice, Nude; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinazolines; Radiation Tolerance; Radiation-Sensitizing Agents; Receptor, Epidermal Growth Factor; Receptor, ErbB-2; Signal Transduction; Urinary Bladder Neoplasms
Publisher
American Association for Cancer Research Inc.
Type
journal article