PDGFRβ reverses EphB4 signaling in alveolar rhabdomyosarcoma

M. Imran Aslam, Jinu Abraham, Atiya Mansoor, Brian J. Druker, Jeffrey W. Tyner, Charles Keller

Resultado de la investigación: Articlerevisión exhaustiva

27 Citas (Scopus)


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, PDGFRβ, 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 PDGFRβ; instead, apoptosis was paradoxically induced. Finally, we showed that smallmolecule inhibition of both PDGFRβ 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 PDGFRβ 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.

Idioma originalEnglish (US)
Páginas (desde-hasta)6383-6388
Número de páginas6
PublicaciónProceedings of the National Academy of Sciences of the United States of America
EstadoPublished - abr 29 2014

ASJC Scopus subject areas

  • General


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