Targeting epidermal growth factor receptor/human epidermal growth factor receptor 2 signalling pathway by a dual receptor tyrosine kinase inhibitor afatinib for radiosensitisation in murine bladder carcinoma |
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Authors: | Yu-Chieh Tsai Chih-Hsien Yeh Kai-Yuan Tzen Pei-Yin Ho Tsung-Fan Tuan Yeong-Shiau Pu Ann-Lii Cheng Jason Chia-Hsien Cheng |
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Affiliation: | 1. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan;2. Department of Nuclear Medicine, National Taiwan University Hospital, Taipei, Taiwan;3. Department of Urology, National Taiwan University Hospital, Taipei, Taiwan;4. Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan;5. Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan;6. Molecular Imaging Center, National Taiwan University, Taipei, Taiwan |
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Abstract: | Given the promising control of bladder cancer achieved by combined chemotherapy/radiotherapy with selective transurethral resection, obstacles remain to the treatment of unresectable bladder cancer. The aim of this study was to determine whether targeting epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) can radiosensitise a murine bladder tumour (MBT-2) cell line. Cell survival, expression of signal proteins and cell cycle changes in MBT-2 cells treated in vitro and in vivo with afatinib, an irreversible EGFR/HER2 inhibitor, plus radiotherapy were investigated by colony formation assay, Western blot assay and flow cytometry, respectively. Ectopic xenografts were established by subcutaneous injection of MBT-2 cells in C3H/HeN mice. Mice were randomised into 4 groups to receive afatinib (10 mg/kg/day on day 1–7) and/or radiotherapy (15 Gy on day 4). Positron emission tomography (PET) on day 8 was used to evaluate the early treatment response. Afatinib (200–1000 nM) increased cell killing by radiation (0–10 Gy). Pre-treatment of irradiated cells with afatinib inhibited radiation-activated HER2 and EGFR phosphorylation. As compared to either treatment alone, the combination increased the level of the cleavage form of poly (ADP-ribose) polymerase, the expression of phospho-γH2AX and the percentage of cells in subG1 phase (indicating enhanced induction of apoptosis), and decreased tumour metabolism and inhibited tumour growth by 64%. Afatinib has therapeutic value as a radiosensitiser of murine bladder cancer cells. The synergism between afatinib and radiation likely enhances DNA damage, leading to increased cell apoptosis. |
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