title: PDGFRβ reverses EphB4 signaling in alveolar rhabdomyosarcoma.
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, 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 small-molecule 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.
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239.
authors.forename: M Imran
authors.initials: MI
authors.lastname: Aslam
authors.forename: Jinu
authors.initials: J
authors.lastname: Abraham
authors.forename: Atiya
authors.initials: A
authors.lastname: Mansoor
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.forename: Charles
authors.initials: C
authors.lastname: Keller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077214:Becaplermin; D001549:Benzamides / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D036388:Ephrin-B2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D051761:Paired Box Transcription Factors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D020239:Receptor Cross-Talk / Q000187:drug effects; D036224:Receptor, EphB4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018232:Rhabdomyosarcoma, Alveolar / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D001549:Benzamides; D036388:Ephrin-B2; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D051761:Paired Box Transcription Factors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D034741:RNA, Small Interfering; D013844:Thiazoles; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D036224:Receptor, EphB4; D020797:Receptor, Platelet-Derived Growth Factor beta; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000069439:Dasatinib
keywords: muscle; pediatric; sarcoma
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