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Research Papers:

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

Kristian W. Pajtler _, Natalie Sadowski, Sandra Ackermann, Kristina Althoff, Kerstin Schönbeck, Katharina Batzke, Simon Schäfers, Andrea Odersky, Lukas Heukamp, Kathy Astrahantseff, Annette Künkele, Hedwig E. Deubzer, Alexander Schramm, Annika Sprüssel, Theresa Thor, Sven Lindner, Angelika Eggert, Matthias Fischer and Johannes H. Schulte

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Oncotarget. 2017; 8:6730-6741. https://doi.org/10.18632/oncotarget.14268

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Abstract

Kristian W. Pajtler1,2,3, Natalie Sadowski4, Sandra Ackermann5, Kristina Althoff4, Kerstin Schönbeck6, Katharina Batzke4, Simon Schäfers4, Andrea Odersky4, Lukas Heukamp7,8, Kathy Astrahantseff6, Annette Künkele6, Hedwig E. Deubzer6, Alexander Schramm4, Annika Sprüssel6,9,10, Theresa Thor4,11,12, Sven Lindner4, Angelika Eggert6,9,10, Matthias Fischer5,13, Johannes H. Schulte6,9,10,14

1Department of Physiology, Medical School, Institute for Medical Sciences, Chonbuk National University, Jeonju, Republic of Korea

2Department of Pediatric Oncology, Hematology and Immunology, University Hospital, Heidelberg, Germany

3German Cancer Consortium (DKTK Core Center Heidelberg), Germany

4Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany

5Department of Pediatric Oncology and Hematology, University Children’s Hospital, and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany

6Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany

7NEO New Oncology, Cologne, Germany

8Institute for Hematopathology, Hamburg, Germany

9Berlin Institute of Health (BIH), Germany

10German Cancer Consortium (DKTK Berlin), Germany

11German Cancer Consortium (DKTK Essen), Germany

12Translational Neuro-Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany

13Medical Faculty, University of Cologne, Cologne, Germany

14German Cancer Research Center (DKFZ), Heidelberg, Germany

Correspondence to:

Johannes H. Schulte, email: johannes.schulte@uni-due.de

Keywords: polo-like kinase 1, pediatric solid tumors, targeted therapy, MYCN

Received: June 18, 2016    Accepted: November 30, 2016    Published: December 27, 2016

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.


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