Abstract
The Wnt/β-catenin pathway’s significance in cancer initiation, progression, and stem cell biology underscores its therapeutic potential. However, the clinical application of Wnt inhibitors remains limited due to challenges posed by off-target effects and complex cross-talk of Wnt signaling with other pathways. In this study, we leveraged a zebrafish model to perform a robust and rapid drug screening of 773 FDA-approved compounds to identify Wnt/β-catenin inhibitors with minimal toxicity. Utilizing zebrafish expressing a Wnt reporter, we identified several drugs that suppressed Wnt signaling without compromising zebrafish development. The effi- cacy of the top hit, Erlotinib, extended to human cells, where it blocked Wnt/β-catenin signaling downstream of the destruction complex. Notably, Erlotinib treatment reduced self-renewal in human T-cell Acute Lymphoblastic Leukemia cells, which rely on active β-catenin signaling for maintenance of leukemia-initiating cells. Erlotinib also reduced leukemia-initiating cell frequency and delayed disease formation in zebrafish models. This study underscores zebrafish’s translational potential in drug discovery and repurposing and highlights a new use for Erlotinib as a Wnt inhibitor for cancers driven by aberrant Wnt/β-catenin signaling.
Document Type
Article
Publication Date
2024
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.biopha.2023.116013
Funding Information
Funding for this research was provided by the National Cancer Institute (R37CA227656 to JSB), the Kentucky Pediatric Cancer Research Trust Fund (research grant to JSB). Salary support was pro- vided to AHC by the NIH National Cancer for Advancing Translational Sciences through grant UL1TR001998. This research was also supported by the Redox Metabolism and the Flow Cytometry and Immune Moni- toring Shared Resources of the University of Kentucky Markey Cancer Center (P30CA177558).
Repository Citation
Al-Hamaly, Majd A.; Cox, Anna H.; Haney, Meghan G.; Zhang, Wen; Arvin, Emma C.; Sampathi, Shilpa; Wimsett, Mary; Liu, Chunming; and Blackburn, Jessica S., "Zebrafish drug screening identifies Erlotinib as an inhibitor of Wnt/ β-catenin signaling and self-renewal in T-cell acute lymphoblastic leukemia" (2024). Markey Cancer Center Faculty Publications. 187.
https://uknowledge.uky.edu/markey_facpub/187
Included in
Animal Experimentation and Research Commons, Cancer Biology Commons, Cells Commons, Oncology Commons
Notes/Citation Information
0753-3322/© 2023 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).