Targeting EIF4A1 is effective against human intrahepatic cholangiocarcinoma
Dysregulation of the translational machinery is a hallmark of cancer, often linked to tumor progression and poor prognosis. This study underscores the potential of zotatifin, a specific inhibitor of EIF4A1 (an essential component of translation initiation) to inhibit the growth of iCCA cells. In addition, zotatifin demonstrated a synergistic effect when used in combination with the Bcl-xl inhibitors A-1155463 and DT2216, significantly enhancing cell apoptosis. Although this investigation did not include an <i>in vivo</i> model, its results, derived from iCCA cell lines, patient-derived organoids, and CAFs, are consistent with the encouraging preliminary results of zotatifin in clinical trials. From a clinical standpoint, these results suggest that zotatifin improves patient outcomes by inhibiting iCCA growth and reducing tumor aggressiveness. Furthermore, combining zotatifin with other drugs could represent a promising therapeutic strategy for targeting iCCA.
Authors
- Ezgi Cibali (ORCID: https://orcid.org/0000-0001-7747-5942)
- Luc J. W. van der Laan (ORCID: https://orcid.org/0000-0002-0651-5334)
- Claudia Fischer
- Sara Steinmann (ORCID: https://orcid.org/0000-0001-9284-1138)
- Elena Antinoro Pizzuto (ORCID: https://orcid.org/0009-0002-9834-4356)
- Isabella Gigante (ORCID: https://orcid.org/0000-0003-3712-4149)
- Anna Lena Saborowski (ORCID: https://orcid.org/0000-0003-4857-4276)
- Monique M.A. Verstegen (ORCID: https://orcid.org/0000-0001-9908-6673)
- Giovanni Mario Pes (ORCID: https://orcid.org/0000-0003-3265-2823)
- Antonio Cigliano (ORCID: https://orcid.org/0000-0002-6408-3613)
- Grazia Galleri (ORCID: https://orcid.org/0000-0001-5379-9387)
- Heiko Siegmund
- Gianluigi Giannelli (ORCID: https://orcid.org/0000-0002-5140-8060)
- Marina Serra (ORCID: https://orcid.org/0000-0001-6916-882X)
- Diego F. Calvisi (ORCID: https://orcid.org/0000-0002-6038-8567)
- Matthias Evert (ORCID: https://orcid.org/0009-0004-3978-8058)
- Wunan Mi
- Denise Schloesser
Institutions
- University of Sassari (IT)
- University of Cagliari (IT)
- Erasmus MC (NL)
- Medizinische Hochschule Hannover (DE)
- Gastroenterology Hospital "Saverio de Bellis" (IT)
- University of Regensburg (DE)
Publication Details
- Journal
- JHEP Reports
- Published
- 2025-04-06
- DOI
- https://doi.org/10.1016/j.jhepr.2025.101416
- Citations
- 1
- Primary Topic
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Type
- article
- Field-Weighted Citation Impact
- 2.01
Funders
- Fondazione di Sardegna
- Honda Development and Manufacturing of America
- Deutsche Forschungsgemeinschaft
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- China Scholarship Council
- Associazione Italiana per la Ricerca sul Cancro
- Deutsche Krebshilfe