RRC ID 79101
Author Al-Hamaly MA, Cox AH, Haney MG, Zhang W, Arvin EC, Sampathi S, Wimsett M, Liu C, Blackburn JS.
Title Zebrafish drug screening identifies Erlotinib as an inhibitor of Wnt/β-catenin signaling and self-renewal in T-cell acute lymphoblastic leukemia.
Journal Biomed Pharmacother
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 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 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.
Volume 170
Pages 116013
Published 2024-1-1
DOI 10.1016/j.biopha.2023.116013
PII S0753-3322(23)01811-5
PMID 38104416
PMC PMC10833092
MeSH Animals Drug Evaluation, Preclinical Erlotinib Hydrochloride / pharmacology Erlotinib Hydrochloride / therapeutic use Humans Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy T-Lymphocytes / metabolism Wnt Signaling Pathway* Zebrafish / metabolism beta Catenin / metabolism
Resource
Zebrafish Tg(6xTcf/LefBS-miniP:d2EGFP)