Oncotarget

Research Papers:

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

Carina Lotz-Jenne, Urs Lüthi, Sabine Ackerknecht, François Lehembre, Tobias Fink, Manuel Stritt, Matthias Wirth, Simona Pavan, Ruben Bill, Urs Regenass, Gerhard Christofori and Nathalie Meyer-Schaller _

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Oncotarget. 2016; 7:25983-26002. https://doi.org/10.18632/oncotarget.8418

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Abstract

Carina Lotz-Jenne1,*, Urs Lüthi1,*, Sabine Ackerknecht1, François Lehembre1, Tobias Fink1, Manuel Stritt1, Matthias Wirth1,3, Simona Pavan2, Ruben Bill2, Urs Regenass1, Gerhard Christofori2, Nathalie Meyer-Schaller2

1Actelion Pharmaceuticals Ltd., Allschwil, Switzerland

2Department of Biomedicine, University of Basel, Basel, Switzerland

3Current address: European Patent Office, Rijswijk, The Netherlands

*These authors contributed equally to this work

Correspondence to:

Nathalie Meyer-Schaller, e-mail: [email protected]

Keywords: EMT, TGFβ, cytoskeleton, ROCK, receptor tyrosine kinase

Received: November 03, 2015     Accepted: March 10, 2016     Published: March 27, 2016

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.


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