| 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
|
| IF |
4.545
|
| Resource |
| Zebrafish |
Tg(6xTcf/LefBS-miniP:d2EGFP) |
