Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma.
Autor: | Myint KZ; Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand., Sueca-Comes M; Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom., Collier P; Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom., Balasubramanian B; Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand., Venkatraman S; Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand., Gordan J; Department of Medicine, University of California, San Francisco, San Francisco, CA, United States., Zaitoun AM; Department of Pathology, Nottingham Universities National Health Service (NHS) Hospital Trust, Queens Medical Centre, Nottingham, United Kingdom., Mukherjee A; Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.; Department of Pathology, Nottingham Universities National Health Service (NHS) Hospital Trust, Queens Medical Centre, Nottingham, United Kingdom., Arora A; Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom.; Department of Medical Oncology, Nottingham Universities National Health Service (NHS) Hospital Trust, Queens Medical Centre, Nottingham, United Kingdom., Larbcharoensub N; Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand., Suriyonplengsaeng C; Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand., Wongprasert K; Department of Anatomy, Faculty of Science, Mahidol University, Bangkok, Thailand., Janvilisri T; Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, Thailand.; Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand., Gomez D; Department of Hepatobiliary and Pancreatic Surgery, and National Institute of Health Care Research (NIHR) Nottingham Digestive Disease Biomedical Research Unit, University of Nottingham, Nottingham, United Kingdom., Grabowska AM; Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom., Tohtong R; Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand., Bates DO; Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom., Yacqub-Usman K; Division of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United Kingdom. |
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Jazyk: | angličtina |
Zdroj: | Frontiers in oncology [Front Oncol] 2023 Dec 07; Vol. 13, pp. 1184900. Date of Electronic Publication: 2023 Dec 07 (Print Publication: 2023). |
DOI: | 10.3389/fonc.2023.1184900 |
Abstrakt: | Introduction: Bile duct cancer (cholangiocarcinoma, CCA) has a poor prognosis for patients, and despite recent advances in targeted therapies for other cancer types, it is still treated with standard chemotherapy. Anaplastic lymphoma kinase (ALK) has been shown to be a primary driver of disease progression in lung cancer, and ALK inhibitors are effective therapeutics in aberrant ALK-expressing tumors. Aberrant ALK expression has been documented in CCA, but the use of ALK inhibitors has not been investigated. Using CCA cell lines and close-to-patient primary cholangiocarcinoma cells, we investigated the potential for ALK inhibitors in CCA. Methods: ALK, cMET, and ROS1 expression was determined in CCA patient tissue by immunohistochemistry and digital droplet polymerase chain reaction, and that in cell lines was determined by immunoblot and immunofluorescence. The effect on cell viability and mechanism of action of ALK, cMet, and ROS1 inhibitors was determined in CCA cell lines. To determine whether ceritinib could affect primary CCA cells, tissue was taken from four patients with biliary tract cancer, without ALK rearrangement, mutation, or overexpression, and grown in three-dimensional tumor growth assays in the presence or absence of humanized mesenchymal cells. Results: ALK and cMet but not ROS were both upregulated in CCA tissues and cell lines. Cell survival was inhibited by crizotinib, a c-met/ALK/ROS inhibitor. To determine the mechanism of this effect, we tested c-Met-specific and ALK/ROS-specific inhibitors, capmatinib and ceritinib, respectively. Whereas capmatinib did not affect cell survival, ceritinib dose-dependently inhibited survival in all cell lines, with IC Discussion: These results indicate that ceritinib or other ALK/ROS inhibitors could be therapeutically useful in cholangiocarcinoma even in the absence of aberrant ALK/ROS1 expression. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Myint, Sueca-Comes, Collier, Balasubramanian, Venkatraman, Gordan, Zaitoun, Mukherjee, Arora, Larbcharoensub, Suriyonplengsaeng, Wongprasert, Janvilisri, Gomez, Grabowska, Tohtong, Bates and Yacqub-Usman.) |
Databáze: | MEDLINE |
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