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.
Highlights
Neuroblastoma is the most common extracranial solid tumor in childhood [1]
We analyzed the effects of GSK461364, a competitive inhibitor for ATP binding to Polo-like kinase 1 (PLK1), on typical tumorigenic properties of preclinical in vitro and in vivo neuroblastoma models
It is characterized by a broad biological heterogeneity based on molecular genetic variations in MYCN oncogene copy number, chromosomal ploidy changes or partial losses and gains, alterations in neurotrophin receptor expression that correlate to different degrees with clinical outcome [2] and with recurrent mutations in a few genes [3]
Summary
Neuroblastoma is the most common extracranial solid tumor in childhood [1] It is characterized by a broad biological heterogeneity based on molecular genetic variations in MYCN oncogene copy number, chromosomal ploidy changes or partial losses and gains, alterations in neurotrophin receptor expression that correlate to different degrees with clinical outcome [2] and with recurrent mutations in a few genes [3]. Treatment of solid tumors in childhood has significantly improved over the past decades, overall survival in high-risk neuroblastoma patients remains less than 40% despite intensive therapy regimens [1]. Since 40 to 50% of patients initially diagnosed with neuroblastoma must be assigned to the high-risk group [5, 6], treatment of this disease remains challenging for pediatric oncologists and novel therapeutic options are still urgently needed
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