Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma
IntroductionBile 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 progre...
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Frontiers Media S.A.
2023-12-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1184900/full |
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| author | Kyaw Zwar Myint Mireia Sueca-Comes Pamela Collier Brinda Balasubramanian Simran Venkatraman John Gordan Abed M. Zaitoun Abhik Mukherjee Abhik Mukherjee Arvind Arora Arvind Arora Noppadol Larbcharoensub Chinnawut Suriyonplengsaeng Kanokpan Wongprasert Tavan Janvilisri Tavan Janvilisri Dhanny Gomez Anna M. Grabowska Rutaiwan Tohtong David O. Bates Kiren Yacqub-Usman |
| author_facet | Kyaw Zwar Myint Mireia Sueca-Comes Pamela Collier Brinda Balasubramanian Simran Venkatraman John Gordan Abed M. Zaitoun Abhik Mukherjee Abhik Mukherjee Arvind Arora Arvind Arora Noppadol Larbcharoensub Chinnawut Suriyonplengsaeng Kanokpan Wongprasert Tavan Janvilisri Tavan Janvilisri Dhanny Gomez Anna M. Grabowska Rutaiwan Tohtong David O. Bates Kiren Yacqub-Usman |
| author_sort | Kyaw Zwar Myint |
| collection | DOAJ |
| description | IntroductionBile 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.MethodsALK, 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.ResultsALK 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 IC50 ranging from 1 to 9 µM and co-treatments with gemcitabine and cisplatin further sensitized cells, with IC50 ranging from IC50 0.60 to 2.32 µM. Ceritinib did not inhibit cMet phosphorylation but did inhibit ALK phosphorylation. ALK was not mutated in any of these cell lines. Only ceritinib inhibited 3D growth of all four patient samples below mean peak serum concentration, in the presence and absence of mesenchymal cells, whereas crizotinib and capmatinib failed to do this. Ceritinib appeared to exert its effect more through autophagy than apoptosis.DiscussionThese results indicate that ceritinib or other ALK/ROS inhibitors could be therapeutically useful in cholangiocarcinoma even in the absence of aberrant ALK/ROS1 expression. |
| first_indexed | 2024-03-09T02:09:26Z |
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| language | English |
| last_indexed | 2024-03-09T02:09:26Z |
| publishDate | 2023-12-01 |
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| series | Frontiers in Oncology |
| spelling | doaj.art-169ad49512ff4bd2ae8d553a1e4dd8f52023-12-07T14:35:04ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-12-011310.3389/fonc.2023.11849001184900Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinomaKyaw Zwar Myint0Mireia Sueca-Comes1Pamela Collier2Brinda Balasubramanian3Simran Venkatraman4John Gordan5Abed M. Zaitoun6Abhik Mukherjee7Abhik Mukherjee8Arvind Arora9Arvind Arora10Noppadol Larbcharoensub11Chinnawut Suriyonplengsaeng12Kanokpan Wongprasert13Tavan Janvilisri14Tavan Janvilisri15Dhanny Gomez16Anna M. Grabowska17Rutaiwan Tohtong18David O. Bates19Kiren Yacqub-Usman20Graduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, ThailandDivision of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomDivision of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomGraduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, ThailandGraduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, ThailandDepartment of Medicine, University of California, San Francisco, San Francisco, CA, United StatesDepartment of Pathology, Nottingham Universities National Health Service (NHS) Hospital Trust, Queens Medical Centre, Nottingham, United KingdomDivision of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomDepartment of Pathology, Nottingham Universities National Health Service (NHS) Hospital Trust, Queens Medical Centre, Nottingham, United KingdomDivision of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomDepartment of Medical Oncology, Nottingham Universities National Health Service (NHS) Hospital Trust, Queens Medical Centre, Nottingham, United KingdomDepartment of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, ThailandDepartment of Anatomy, Faculty of Science, Mahidol University, Bangkok, ThailandDepartment of Anatomy, Faculty of Science, Mahidol University, Bangkok, ThailandGraduate Program in Molecular Medicine, Faculty of Science, Mahidol University, Bangkok, ThailandDepartment of Biochemistry, Faculty of Science, Mahidol University, Bangkok, ThailandDepartment of Hepatobiliary and Pancreatic Surgery, and National Institute of Health Care Research (NIHR) Nottingham Digestive Disease Biomedical Research Unit, University of Nottingham, Nottingham, United KingdomDivision of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomDepartment of Biochemistry, Faculty of Science, Mahidol University, Bangkok, ThailandDivision of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomDivision of Cancer and Stem Cells, Biodiscovery Institute, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, United KingdomIntroductionBile 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.MethodsALK, 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.ResultsALK 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 IC50 ranging from 1 to 9 µM and co-treatments with gemcitabine and cisplatin further sensitized cells, with IC50 ranging from IC50 0.60 to 2.32 µM. Ceritinib did not inhibit cMet phosphorylation but did inhibit ALK phosphorylation. ALK was not mutated in any of these cell lines. Only ceritinib inhibited 3D growth of all four patient samples below mean peak serum concentration, in the presence and absence of mesenchymal cells, whereas crizotinib and capmatinib failed to do this. Ceritinib appeared to exert its effect more through autophagy than apoptosis.DiscussionThese results indicate that ceritinib or other ALK/ROS inhibitors could be therapeutically useful in cholangiocarcinoma even in the absence of aberrant ALK/ROS1 expression.https://www.frontiersin.org/articles/10.3389/fonc.2023.1184900/fullcholangiocarcinomaOpisthorchis viverrinianaplastic lymphoma kinase 1novel therapeuticscytotoxicity and autophagy |
| spellingShingle | Kyaw Zwar Myint Mireia Sueca-Comes Pamela Collier Brinda Balasubramanian Simran Venkatraman John Gordan Abed M. Zaitoun Abhik Mukherjee Abhik Mukherjee Arvind Arora Arvind Arora Noppadol Larbcharoensub Chinnawut Suriyonplengsaeng Kanokpan Wongprasert Tavan Janvilisri Tavan Janvilisri Dhanny Gomez Anna M. Grabowska Rutaiwan Tohtong David O. Bates Kiren Yacqub-Usman Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma Frontiers in Oncology cholangiocarcinoma Opisthorchis viverrini anaplastic lymphoma kinase 1 novel therapeutics cytotoxicity and autophagy |
| title | Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma |
| title_full | Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma |
| title_fullStr | Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma |
| title_full_unstemmed | Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma |
| title_short | Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma |
| title_sort | preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma |
| topic | cholangiocarcinoma Opisthorchis viverrini anaplastic lymphoma kinase 1 novel therapeutics cytotoxicity and autophagy |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1184900/full |
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