Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation

Authors

• Suchada Phimsen
• Supisara Sripramote
• Jeranan Jantra
• Chaiwat Choeiphuk
• Somkit Mingphruedhi
• Paramin Muangkaew
• Narongsak Rungsakulkij
• Pongsatorn Tangtawee
• Wikran Suragul
• Watoo Vassanasiri Farquharson
• Kanokpan Wongprasert
• Somchai Chutipongtanate
• Pimtip Sanvarinda
• Marisa Ponpuak
• Naravat Poungvarin
• Tavan Janvilisri
• Tuangporn Suthiphongchai
• Kiren Yacqub-Usman
• Anna M Grabowska
• David O Bates
• Rutaiwan Tohtong

Language

English

Publication Date

2-2-2024

Journal

Pharmaceuticals

DOI

10.3390/ph17020197

PMID

38399413

PMCID

PMC10892566

PubMedCentral® Posted Date

2-2-2024

PubMedCentral® Full Text Version

Post-print

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.

Keywords

cholangiocarcinoma, ceritinib, cancer, kinase inhibitors, antitumor agents

Published Open-Access

yes

Recommended Citation

Phimsen, Suchada; Sripramote, Supisara; Jantra, Jeranan; et al., "Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation" (2024). Faculty, Staff and Students Publications. 8449.
https://digitalcommons.library.tmc.edu/baylor_docs/8449