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The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models

Item Type:Article
Title:The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models
Creators Name:Pajtler, K.W. and Sadowski, N. and Ackermann, S. and Althoff, K. and Schönbeck, K. and Batzke, K. and Schäfers, S. and Odersky, A. and Heukamp, L. and Astrahantseff, K. and Künkele, A. and Deubzer, H.E. and Schramm, A. and Sprüssel, A. and Thor, T. and Lindner, S. and Eggert, A. and Fischer, M. and Schulte, J.H.
Abstract:Polo-like kinase 1 (PLK1) is a serine/threonine kinase that promotes G2/M-phase transition, is expressed in elevated levels in high-risk neuroblastomas and correlates with unfavorable patient outcome. Recently, we and others have presented PLK1 as a potential drug target for neuroblastoma, and reported that the BI2536 PLK1 inhibitor showed antitumoral actvity in preclinical neuroblastoma models. Here we analyzed the effects of GSK461364, a competitive inhibitor for ATP binding to PLK1, on typical tumorigenic properties of preclinical in vitro and in vivo neuroblastoma models. GSK461364 treatment of neuroblastoma cell lines reduced cell viability and proliferative capacity, caused cell cycle arrest and massively induced apoptosis. These phenotypic consequences were induced by treatment in the low-dose nanomolar range, and were independent of MYCN copy number status. GSK461364 treatment strongly delayed established xenograft tumor growth in nude mice, and significantly increased survival time in the treatment group. These preclinical findings indicate PLK1 inhibitors may be effective for patients with high-risk or relapsed neuroblastomas with upregulated PLK1 and might be considered for entry into early phase clinical trials in pediatric patients.
Keywords:Polo-Like Kinase 1, Pediatric Solid Tumors, Targeted Therapy, MYCN, Animals, Mice
Publisher:Impact Journals LLC (U.S.A.)
Page Range:6730-6741
Date:24 January 2017
Official Publication:https://doi.org/10.18632/oncotarget.14268
PubMed:View item in PubMed

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