PDGFRbeta reverses EphB4 signaling in alveolar rhabdomyosarcoma.

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Aslam MI, Abraham J, Mansoor A, Druker BJ, Tyner JW, Keller C

PDGFRbeta reverses EphB4 signaling in alveolar rhabdomyosarcoma.

Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):6383-8. doi: 10.1073/pnas.1403608111. Epub 2014 Apr 14.

PubMed ID

24733895 [ View in PubMed

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Abstract

Alveolar rhabdomyosarcoma (aRMS) is an aggressive myogenic childhood malignancy, not infrequently presenting as incurable metastatic disease. To identify therapeutic targets, we performed an unbiased tyrosine kinome RNA interference screen in primary cell cultures from a genetically engineered, conditional mouse model of aRMS. We identified ephrin receptor B4 (EphB4) as a target that is widely expressed in human aRMS and that portends a poor clinical outcome in an expression level-dependent manner. We also uncovered cross-talk of this ephrin receptor with another receptor tyrosine kinase, PDGFRbeta, which facilitates PDGF ligand-dependent, ephrin ligand-independent activation of EphB4 converging on the Akt and Erk1/2 pathways. Conversely, EphB4 activation by its cognate ligand, EphrinB2, did not stimulate PDGFRbeta; instead, apoptosis was paradoxically induced. Finally, we showed that small-molecule inhibition of both PDGFRbeta and EphB4 by dasatinib resulted in a significant decrease in tumor cell viability in vitro, as well as decreased tumor growth rate and significantly prolonged survival in vivo. To our knowledge, these results are the first to identify EphB4 and its cross-talk with PDGFRbeta as unexpected vital determinants of tumor cell survival in aRMS, with EphB4 at the crux of a bivalent signaling node that is either mitogenic or proapoptotic.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Dasatinib	Ephrin type-B receptor 4	Protein	Humans	Unknown	Inhibitor	Details