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Zebrafish Drug Screening Identifies Erlotinib as an Inhibitor of Wnt/β-Catenin Signaling and Self-Renewal in T-cell
Abstract:
The Wnt/β-catenin pathway's 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/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 efficacy 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 are known to 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.
Highlights:
Zebrafish-based drug screening offers an inexpensive and robust platform for identifying compounds with high efficacy and low toxicity in vivo . Erlotinib, 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.The 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.
Insights
Zebrafish drug screening identified Erlotinib as a Wnt/β-catenin inhibitor. This repurposed drug shows promise in reducing cancer stemness and treating cancers driven by aberrant Wnt signaling with minimal toxicity.
Area of Science:
- Oncology
- Pharmacology
- Developmental Biology
Background:
- The Wnt/β-catenin pathway is crucial in cancer and stem cell biology, but Wnt inhibitors face challenges like off-target effects.
- Targeting Wnt signaling is a promising therapeutic strategy for various cancers, including leukemia.
Approach:
- A large-scale drug screen of 773 FDA-approved compounds was conducted using a zebrafish Wnt reporter model.
- The screening prioritized compounds with potent Wnt inhibition and minimal toxicity in vivo.
- Erlotinib was identified as a top hit and its efficacy was validated in human cells and zebrafish cancer models.
Key Points:
- Erlotinib effectively inhibited Wnt/β-catenin signaling downstream of the destruction complex in human T-cell Acute Lymphoblastic Leukemia cells.
- Erlotinib reduced the self-renewal of leukemia-initiating cells and delayed disease progression in zebrafish models.
- The study highlights the potential of drug repurposing and zebrafish models for discovering novel cancer therapies.
Conclusions:
- Zebrafish serve as a valuable translational model for rapid and robust drug screening and repurposing.
- Erlotinib demonstrates a novel application as a Wnt inhibitor for cancers driven by aberrant Wnt/β-catenin signaling.
- This finding offers a new therapeutic avenue for targeting cancer stemness and improving patient outcomes.
