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bioRxiv · 10.1101/2023.08.28.555200

Zebrafish Drug Screening Identifies Erlotinib as an Inhibitor of Wnt/β-Catenin Signaling and Self-Renewal in T-cell Acute Lymphoblastic Leukemia

Al-Hamaly, M. A.·Cox, A. H.·Haney, M. G.·Zhang, W.·Arvin, E. C.·Sampathi, S.·Wimsett, M.·Blackburn, J. S.
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Abstract

The Wnt/{beta}-catenin pathways significance in cancer initiation, progression, and stem cell biology underscores its therapeutic potential, yet clinical application of Wnt inhibitors remains limited due to challenges posed by off-target effects and complex crosstalk with other pathways. In this study, we leveraged the zebrafish model to perform a robust and rapid drug screening of 773 FDA-approved compounds to identify Wnt/{beta}-catenin inhibitors with minimal toxicity. Utilizing zebrafish expressing a Wnt reporter, we identified several drugs that suppressed Wnt signaling without compromising zebrafish development. The efficacy of the top hit, Erlotinib, extended to human cells, where it blocked Wnt/{beta}-catenin signaling downstream of the destruction complex. Notably, Erlotinib treatment reduced self-renewal in human T-cell Acute Lymphoblastic Leukemia cells, which are known to rely on active {beta}-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 zebrafishs translational potential in drug discovery and repurposing, and highlights a new use for Erlotinib as a Wnt inhibitor for cancers driven by aberrant Wnt/{beta}-catenin signaling. HighlightsO_LIZebrafish-based drug screening offers an inexpensive and robust platform for identifying compounds with high efficacy and low toxicity in vivo. C_LIO_LIErlotinib, an Epidermal Growth Factor Receptor (EGFR) inhibitor, emerged as a potent and promising Wnt inhibitor with effects in both zebrafish and human cell-based Wnt reporter assays. C_LIO_LIThe identification of Erlotinib as a Wnt inhibitor underscores the value of repurposed drugs in developing targeted therapies to disrupt cancer stemness and improve clinical outcomes C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=42 SRC="FIGDIR/small/555200v1_ufig1.gif" ALT="Figure 1"> View larger version (14K): org.highwire.dtl.DTLVardef@150e0a0org.highwire.dtl.DTLVardef@cb3455org.highwire.dtl.DTLVardef@d8d8a8org.highwire.dtl.DTLVardef@780535_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Al-Hamaly, M. A., Cox, A. H., Haney, M. G., Zhang, W., Arvin, E. C., Sampathi, S., Wimsett, M., Blackburn, J. S.. 2023-08-28. Zebrafish Drug Screening Identifies Erlotinib as an Inhibitor of Wnt/β-Catenin Signaling and Self-Renewal in T-cell Acute Lymphoblastic Leukemia. https://doi.org/10.1101/2023.08.28.555200

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