title: Synergistic Blockade of EGFR and HER2 by New-Generation EGFR Tyrosine Kinase Inhibitor Enhances Radiation Effect in Bladder Cancer Cells.
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.
authors.affiliation: Department of Oncology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Yu-Chieh
authors.initials: YC
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Pei-Yin
authors.initials: PY
authors.lastname: Ho
authors.affiliation: Department of Nuclear Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Molecular Imaging Center, National Taiwan University, Taipei, Taiwan.
authors.forename: Kai-Yuan
authors.initials: KY
authors.lastname: Tzen
authors.affiliation: Department of Oncology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Tsung-Fan
authors.initials: TF
authors.lastname: Tuan
authors.affiliation: Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Wei-Lin
authors.initials: WL
authors.lastname: Liu
authors.affiliation: Department of Oncology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan. Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
authors.affiliation: Department of Urology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. jasoncheng@ntu.edu.tw yspu@ntu.edu.tw.
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
authors.affiliation: Department of Oncology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan. Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan. Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan. jasoncheng@ntu.edu.tw yspu@ntu.edu.tw.
authors.forename: Jason Chia-Hsien
authors.initials: JC
authors.lastname: Cheng
mesh_terms: D000077716:Afatinib; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000077716:Afatinib; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human