Aurora B kinase is a potent and selective target in MYCN-driven neuroblastoma.
Aurora B kinase is a potent and selective target in MYCN-driven neuroblastoma.
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DOI：
10.18632/oncotarget.6208
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发表时间：
2015-11-03
期刊：
影响因子：
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通讯作者：
Khan J
中科院分区：
文献类型：
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作者：
Bogen D;Wei JS;Azorsa DO;Ormanoglu P;Buehler E;Guha R;Keller JM;Mathews Griner LA;Ferrer M;Song YK;Liao H;Mendoza A;Gryder BE;Sindri S;He J;Wen X;Zhang S;Shern JF;Yohe ME;Taschner-Mandl S;Shohet JM;Thomas CJ;Martin SE;Ambros PF;Khan J
尽管多模式治疗取得了进展，但神经母细胞瘤（NB）对于患有高风险疾病的儿童来说往往是致命的，许多幸存者需要应对高剂量化疗和放疗的长期副作用。为了确定新的治疗靶点，我们对可药物基因组进行了siRNA筛选，并结合了465种化合物的小分子筛选，这些化合物针对4种NB细胞系的39种不同的作用机制。我们在至少一种细胞系中确定了58个基因作为靶标，包括AURKB。在药物筛选中，极光激酶抑制剂（9个分子），特别是aurkb选择性化合物barasertib，对myn扩增细胞系的敏感性是最具歧视性的。在10个NB细胞系的扩展板中，具有myn -扩增和野生型TP53的细胞系对低纳摩尔浓度的barasertib最敏感。在mycn扩增的野生型细胞中，抑制AURKB激酶活性导致已知靶点组蛋白H3磷酸化降低，TP53上调。然而，在AURKB抑制作用下，野生型和TP53突变型mycn扩增细胞系在G2/M期阻滞。此外，barasertib诱导内复制和细胞凋亡。mycn扩增/TP53野生型神经母细胞瘤异种移植治疗可显著抑制生长和肿瘤消退。因此，极光B激酶抑制在侵袭性神经母细胞瘤中非常有效，值得在临床试验中进一步研究。
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.