Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation
Issued Date
2024-02-01
Resource Type
eISSN
14248247
Scopus ID
2-s2.0-85187218843
Journal Title
Pharmaceuticals
Volume
17
Issue
2
Rights Holder(s)
SCOPUS
Bibliographic Citation
Pharmaceuticals Vol.17 No.2 (2024)
Suggested Citation
Myint K.Z., Balasubramanian B., Venkatraman S., Phimsen S., Sripramote S., Jantra J., Choeiphuk C., Mingphruedhi S., Muangkaew P., Rungsakulkij N., Tangtawee P., Suragul W., Farquharson W.V., Wongprasert K., Chutipongtanate S., Sanvarinda P., Ponpuak M., Poungvarin N., Janvilisri T., Suthiphongchai T., Yacqub-Usman K., Grabowska A.M., Bates D.O., Tohtong R. Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation. Pharmaceuticals Vol.17 No.2 (2024). doi:10.3390/ph17020197 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/97656
Title
Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation
Author(s)
Myint K.Z.
Balasubramanian B.
Venkatraman S.
Phimsen S.
Sripramote S.
Jantra J.
Choeiphuk C.
Mingphruedhi S.
Muangkaew P.
Rungsakulkij N.
Tangtawee P.
Suragul W.
Farquharson W.V.
Wongprasert K.
Chutipongtanate S.
Sanvarinda P.
Ponpuak M.
Poungvarin N.
Janvilisri T.
Suthiphongchai T.
Yacqub-Usman K.
Grabowska A.M.
Bates D.O.
Tohtong R.
Balasubramanian B.
Venkatraman S.
Phimsen S.
Sripramote S.
Jantra J.
Choeiphuk C.
Mingphruedhi S.
Muangkaew P.
Rungsakulkij N.
Tangtawee P.
Suragul W.
Farquharson W.V.
Wongprasert K.
Chutipongtanate S.
Sanvarinda P.
Ponpuak M.
Poungvarin N.
Janvilisri T.
Suthiphongchai T.
Yacqub-Usman K.
Grabowska A.M.
Bates D.O.
Tohtong R.
Corresponding Author(s)
Other Contributor(s)
Abstract
Cholangiocarcinoma (CCA) is a difficult-to-treat cancer, with limited therapeutic options and surgery being the only curative treatment. Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients. Receptor tyrosine kinases (RTKs) are aberrantly expressed in CCAs encompassing potential therapeutic opportunity. Hence, 112 RTK inhibitors were screened in KKU-M213 cells, and ceritinib, an approved targeted therapy for ALK-fusion gene driven cancers, was the most potent candidate. Ceritinib’s cytotoxicity in CCA was assessed using MTT and clonogenic assays, along with immunofluorescence, western blot, and qRT-PCR techniques to analyze gene expression and signaling changes. Furthermore, the drug interaction relationship between ceritinib and cisplatin was determined using a ZIP synergy score. Additionally, spheroid and xenograft models were employed to investigate the efficacy of ceritinib in vivo. Our study revealed that ceritinib effectively killed CCA cells at clinically relevant plasma concentrations, irrespective of ALK expression or mutation status. Ceritinib modulated multiple signaling pathways leading to the inhibition of the PI3K/Akt/mTOR pathway and activated both apoptosis and autophagy. Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations.