Priority Research Papers:
Aurora B kinase is a potent and selective target in MYCN-driven neuroblastoma
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Dominik Bogen1,2,*, Jun S. Wei1,*, David O. Azorsa4, Pinar Ormanoglu3, Eugen Buehler3, Rajarshi Guha3, Jonathan M. Keller3, Lesley A. Mathews Griner3, Marc Ferrer3, Young K. Song1, Hongling Liao1, Arnulfo Mendoza5, Berkley E. Gryder1, Sivasish Sindri1, Jianbin He1, Xinyu Wen1, Shile Zhang1, John F. Shern1, Marielle E. Yohe1, Sabine Taschner-Mandl2, Jason M. Shohet6, Craig J. Thomas3, Scott E. Martin3, Peter F. Ambros2 and Javed Khan1
1 Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
2 Children’s Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria
3 Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
4 Clinical Translational Research Division, Translational Genomics Research Institute (TGen), Scottsdale, AZ, USA
5 Tumor and Metastasis Biology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
6 Texas Children’s Cancer Center and Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
* These authors have contributed equally to this work
Javed Khan, email:
Keywords: neuroblastoma, MYCN, AURKB, high-throughput screening, barasertib
Received: May 27, 2015 Accepted: September 30, 2015 Published: October 21, 2015
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.
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