The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models
Metrics: PDF 1695 views | HTML 1915 views | ?
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
Johannes H. Schulte, email: firstname.lastname@example.org
Keywords: polo-like kinase 1, pediatric solid tumors, targeted therapy, MYCN
Received: June 18, 2016 Accepted: November 30, 2016 Published: December 27, 2016
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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.