title: The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models.
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.
authors.affiliation: Department of Physiology, Medical School, Institute for Medical Sciences, Chonbuk National University, Jeonju, Republic of Korea.|Department of Pediatric Oncology, Hematology and Immunology, University Hospital, Heidelberg, Germany.|German Cancer Consortium (DKTK Core Center Heidelberg), Germany.
authors.forename: Kristian W
authors.initials: KW
authors.lastname: Pajtler
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Sadowski
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital, and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ackermann
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Althoff
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schönbeck
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Batzke
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Schäfers
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Odersky
authors.affiliation: NEO New Oncology, Cologne, Germany.|Institute for Hematopathology, Hamburg, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Heukamp
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Kathy
authors.initials: K
authors.lastname: Astrahantseff
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Künkele
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany.
authors.forename: Hedwig E
authors.initials: HE
authors.lastname: Deubzer
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany.|Berlin Institute of Health (BIH), Germany.|German Cancer Consortium (DKTK Berlin), Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Sprüssel
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany.|German Cancer Consortium (DKTK Essen), Germany.|Translational Neuro-Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Theresa
authors.initials: T
authors.lastname: Thor
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children`s Hospital Essen, Essen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Lindner
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany.|Berlin Institute of Health (BIH), Germany.|German Cancer Consortium (DKTK Berlin), Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital, and Center for Molecular Medicine Cologne (CMMC), Cologne, Germany.|Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Germany.|Berlin Institute of Health (BIH), Germany.|German Cancer Consortium (DKTK Berlin), Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D018628:Gene Dosage; D006801:Humans; D020128:Inhibitory Concentration 50; D008819:Mice, Nude; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics; D009447:Neuroblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013876:Thiophenes / Q000494:pharmacology*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D018797:Cell Cycle Proteins; D000071447:N-Myc Proto-Oncogene Protein; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013876:Thiophenes; D000097869:Polo-Like Kinase 1; C561573:GSK 461364; C459801:MYCN protein, human
keywords: MYCN; pediatric solid tumors; polo-like kinase 1; targeted therapy