1. Aurora B kinase is a potent and selective target in MYCN-driven neuroblastoma
- Author
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Jonathan M. Keller, Dominik Bogen, Hongling Liao, Young K. Song, Berkley E. Gryder, Rajarshi Guha, Eugen Buehler, Craig J. Thomas, Javed Khan, Shile Zhang, David O. Azorsa, Arnulfo Mendoza, Jason M. Shohet, Pinar Ormanoglu, Jianbin He, Marielle E. Yohe, Sivasish Sindri, Xinyu Wen, Scott E. Martin, Jun S. Wei, Marc Ferrer, John F. Shern, Peter F. Ambros, Lesley A. Mathews Griner, and Sabine Taschner-Mandl
- Subjects
Aurora B kinase ,Apoptosis ,Mice, SCID ,high-throughput screening ,Small Molecule Libraries ,chemistry.chemical_compound ,Histone H3 ,Mice ,neuroblastoma ,Aurora kinase ,Mice, Inbred NOD ,Neuroblastoma ,Cell Line, Tumor ,MYCN ,Endoreduplication ,Medicine ,Animals ,Aurora Kinase B ,Humans ,Molecular Targeted Therapy ,Kinase activity ,neoplasms ,Protein Kinase Inhibitors ,Genetics ,business.industry ,AURKB ,High-Throughput Nucleotide Sequencing ,medicine.disease ,Xenograft Model Antitumor Assays ,barasertib ,Oncology ,chemistry ,Gene Knockdown Techniques ,Cancer research ,Female ,RNA Interference ,Growth inhibition ,business ,Priority Research Paper - 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.
- Published
- 2015