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A high-content EMT screen identifies multiple receptor tyrosine kinase inhibitors with activity on TGFβ receptor

Lotz-Jenne, Carina and Lüthi, Urs and Ackerknecht, Sabine and Lehembre, François and Fink, Tobias and Stritt, Manuel and Wirth, Matthias and Pavan, Simona and Bill, Ruben and Regenass, Urs and Christofori, Gerhard and Meyer-Schaller, Nathalie. (2016) A high-content EMT screen identifies multiple receptor tyrosine kinase inhibitors with activity on TGFβ receptor. Oncotarget, 7 (18). pp. 25983-26002.

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Official URL: https://edoc.unibas.ch/61448/

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Abstract

An epithelial to mesenchymal transition (EMT) enables epithelial tumor cells to break out of the primary tumor mass and to metastasize. Understanding the molecular mechanisms driving EMT in more detail will provide important tools to interfere with the metastatic process. To identify pharmacological modulators and druggable targets of EMT, we have established a novel multi-parameter, high-content, microscopy-based assay and screened chemical compounds with activities against known targets. Out of 3423 compounds, we have identified 19 drugs that block transforming growth factor beta (TGFβ)-induced EMT in normal murine mammary gland epithelial cells (NMuMG). The active compounds include inhibitors against TGFβ receptors (TGFBR), Rho-associated protein kinases (ROCK), myosin II, SRC kinase and uridine analogues. Among the EMT-repressing compounds, we identified a group of inhibitors targeting multiple receptor tyrosine kinases, and biochemical profiling of these multi-kinase inhibitors reveals TGFBR as a thus far unknown target of their inhibitory spectrum. These findings demonstrate the feasibility of a multi-parameter, high-content microscopy screen to identify modulators and druggable targets of EMT. Moreover, the newly discovered "off-target" effects of several receptor tyrosine kinase inhibitors have important consequences for in vitro and in vivo studies and might beneficially contribute to the therapeutic effects observed in vivo.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Tumor Biology (Christofori)
UniBasel Contributors:Christofori, Gerhard M.
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1949-2553
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:19 Mar 2019 17:53
Deposited On:19 Mar 2019 17:53

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