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Cancer Research and Treatment > Accepted Articles
doi: https://doi.org/10.4143/crt.2020.585    [Accepted]
Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells
Boonyakorn Boonsri1, Kiren Yacqub-Usman2, Pakpoom Thintharua1, Kyaw Zwar Myint3, Thannicha Sae-Lao4, Pam Collier2, Chinnawut Suriyonplengsaeng1, Noppadol Larbcharoensub5, Brinda Balasubramanian6, Simran Venkatraman6, Isioma U. Egbuniwe2,7, Dhanwant Gomez8, Abhik Mukherjee2,7, Supeecha Kumkate9, Tavan Janvilisri3, Abed M Zaitoun7, Thiti Kuakpaetoon10, Rutaiwan Tohtong3, Anna M Grabowska2, David O. Bates2, Kanokpan Wongprasert1
1Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand
2Division of Cancer and Stem Cells, Centre for Cancer Sciences, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
3Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand
4Department of Anatomy, Faculty of Medicine, Siam University, Bangkok, Thailand
5Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
6Molecular Medicine Program, Multidisciplinary Unit, Faculty of Science, Mahidol University, Bangkok, Thailand
7Department of Cellular Pathology, Queen’s Medical Centre, Nottingham University Hospitals NHS Trust, Nottingham, UK
8Department of Hepatobiliary and Pancreatic Surgery, and NIHR Nottingham Digestive Disease Biomedical Research Unit, University of Nottingham, Nottingham, UK
9Department of Biology, Faculty of Science, Mahidol University, Bangkok, Thailand
10Department of Pathology, Rajavithi Hospital, Bangkok, Thailand
Correspondence  David O. Bates ,Tel: 44-1158231135, Email: david.bates@nottingham.ac.uk
Kanokpan Wongprasert ,Tel: 66-2201-5412, Email: kanokpan.won@mahidol.ac.th
Received: June 17, 2020;  Accepted: October 5, 2020.  Published online: October 7, 2020.
*Boonyakorn Boonsri and Kiren Yacqub-Usman contributed equally to this work.
The potential of members of the epidermal growth factor receptor (ErbB) family as drug targets in cholangiocarcinoma (CCA) has not been extensively addressed. Although phase III clinical trials showed no survival benefits of erlotinib in patients with advanced CCA, the outcome of the standard-of-care chemotherapy treatment for CCA, gemcitabine/cisplatin, is discouraging so we determined the effect of other ErbB receptor inhibitors alone or in conjunction with chemotherapy in CCA cells.
Materials and Methods
ErbB receptor expression was determined in CCA patient tissues by immunohistochemistry and digital-droplet polymerase chain reaction, and in primary cells and cell lines by immunoblot. Effects on cell viability and cell cycle distribution of combination therapy using ErbB inhibitors with chemotherapeutic drugs was carried out in CCA cell lines. 3D culture of primary CCA cells was then adopted to evaluate the drug effect in a setting that more closely resembles in vivo cell environments.
CCA tumors showed higher expression of all ErbB receptors compared with resection margins. Primary and CCA cell lines had variable expression of erbB receptors. CCA cell lines showed decreased cell viability when treated with chemotherapeutic drugs (gemcitabine and 5-fluorouracil) but also with ErbB inhibitors, particularly afatinib, and with a combination. Sequential treatment of gemcitabine with afatinib was particularly effective. Co-culture of CCA primary cells with cancer-associated fibroblasts decreased sensitivity to chemotherapies, but sensitized to afatinib.
Afatinib is a potential epidermal growth factor receptor targeted drug for CCA treatment and sequential treatment schedule of gemcitabine and afatinib could be explored in CCA patients.
Key words: Cholangiocarcinoma, ErbB receptors, ErbB targeted drugs, Antineoplastic agents, Gemcitabine, Afatinib
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