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

Authors

  • K.W. Pajtler
  • N. Sadowski
  • S. Ackermann
  • K. Althoff
  • K. Schönbeck
  • K. Batzke
  • S. Schäfers
  • A. Odersky
  • L. Heukamp
  • K. Astrahantseff
  • A. Künkele
  • H.E. Deubzer
  • A. Schramm
  • A. Sprüssel
  • T. Thor
  • S. Lindner
  • A. Eggert
  • M. Fischer
  • J.H. Schulte

Journal

  • Oncotarget

Citation

  • Oncotarget 8 (4): 6730-6741

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.


DOI

doi:10.18632/oncotarget.14268