Abstract
Despite advances in multimodal treatment, neuroblastoma (NB) is often fatal for children with high-risk disease and many survivors need to cope with long-term side effects from high-dose chemotherapy and radiation. To identify new therapeutic targets, we performed an siRNA screen of the druggable genome combined with a small molecule screen of 465 compounds targeting 39 different mechanisms of actions in four NB cell lines. We identified 58 genes as targets, including AURKB, in at least one cell line. In the drug screen, aurora kinase inhibitors (nine molecules) and in particular the AURKB-selective compound, barasertib, were the most discriminatory with regard to sensitivity for MYCN-amplified cell lines. In an expanded panel of ten NB cell lines, those with MYCN-amplification and wild-type TP53 were the most sensitive to low nanomolar concentrations of barasertib. Inhibition of the AURKB kinase activity resulted in decreased phosphorylation of the known target, histone H3, and upregulation of TP53 in MYCN-amplified, TP53 wild-type cells. However, both wild-type and TP53 mutant MYCN-amplified cell lines arrested in G2/M phase upon AURKB inhibition. Additionally, barasertib induced endoreduplication and apoptosis. Treatment of MYCN-amplified/TP53 wild-type neuroblastoma xenografts resulted in profound growth inhibition and tumor regression. Therefore, aurora B kinase inhibition is highly effective in aggressive neuroblastoma and warrants further investigation in clinical trials.
Highlights
Neuroblastoma (NB) is a solid tumor of the peripheral nervous system occurring mostly in infants and younger children
The importance of AURKB was demonstrated by the decrease of cell viability after AURKB knockdown in 4 NB cell lines and supported by our discovery of numerous vulnerability genes which interact with the mitotic kinase and the chromosomal passenger complex (CPC)
By screening a collection of oncology-relevant small molecules in parallel, we identified the AURKB-selective inhibitor barasertib and seven other classes of agents that inhibit other vulnerability genes discovered in the RNAi experiments
Summary
Neuroblastoma (NB) is a solid tumor of the peripheral nervous system occurring mostly in infants and younger children. Accounting for 8-10% of all childhood tumors, NB is responsible for 10-12% of cancer-related www.impactjournals.com/oncotarget deaths in children [1, 2]. Advances in biologybased multimodal treatment strategies have led to an improved outcome for NB patients in the recent decades [2], survival rates for advanced-stage neuroblastoma remain poor ( < 50%) due to the clinical and biological heterogeneity of the cancer and a lack of adequate treatment options [3]. Development of targeted treatment approaches has been challenging due to the heterogeneous nature of this cancer and an insufficient understanding of the biology of high-risk neuroblastoma. The anaplastic lymphoma receptor tyrosine kinase, ALK, is mutated in approximately 10% of all spontaneous cases and currently the only therapeutically-targetable receptor tyrosine kinase in neuroblastoma [5]
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