Aurora B kinase is a potent and selective target in MYCN-driven neuroblastoma.
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.
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
Dominik
D
Bogen
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Jun S
JS
Wei
Clinical Translational Research Division, Translational Genomics Research Institute (TGen), Scottsdale, AZ, USA.
David O
DO
Azorsa
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Pinar
P
Ormanoglu
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Eugen
E
Buehler
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Rajarshi
R
Guha
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Jonathan M
JM
Keller
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Lesley A
LA
Mathews Griner
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Marc
M
Ferrer
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Young K
YK
Song
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Hongling
H
Liao
Tumor and Metastasis Biology Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Arnulfo
A
Mendoza
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Berkley E
BE
Gryder
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Sivasish
S
Sindri
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Jianbin
J
He
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Xinyu
X
Wen
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Shile
S
Zhang
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
John F
JF
Shern
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Marielle E
ME
Yohe
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
Sabine
S
Taschner-Mandl
Texas Children's Cancer Center and Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
Jason M
JM
Shohet
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Craig J
CJ
Thomas
Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Scott E
SE
Martin
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
Peter F
PF
Ambros
Oncogenomics Section, Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Javed
J
Khan
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D054852:Small Molecule Libraries / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D064107:Aurora Kinase B
AURKB; MYCN; barasertib; high-throughput screening; neuroblastoma