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PIM kinases are a potential prognostic biomarker and therapeutic target in neuroblastoma
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2018-02-13 , DOI: 10.1158/1535-7163.mct-17-0868
Diede Brunen 1 , Romy C. de Vries 1 , Cor Lieftink 1 , Roderick L. Beijersbergen 1 , René Bernards 1
Affiliation  

The majority of high-risk neuroblastoma patients are refractory to, or relapse on, current treatment regimens, resulting in 5-year survival rates of less than 50%. This emphasizes the urgent need to identify novel therapeutic targets. Here, we report that high PIM kinase expression is correlated with poor overall survival. Treatment of neuroblastoma cell lines with the pan-PIM inhibitors AZD1208 or PIM-447 suppressed proliferation through inhibition of mTOR signaling. In a panel of neuroblastoma cell lines, we observed a marked binary response to PIM inhibition, suggesting that specific genetic lesions control responses to PIM inhibition. Using a genome-wide CRISPR-Cas9 genetic screen, we identified NF1 loss as the major resistance mechanism to PIM kinase inhibitors. Treatment with AZD1208 impaired the growth of NF1 wild-type xenografts, while NF1 knockout cells were insensitive. Thus, our data indicate that PIM inhibition may be a novel targeted therapy in NF1 wild-type neuroblastoma. Mol Cancer Ther; 17(4); 849–57. ©2018 AACR.

中文翻译:

PIM 激酶是神经母细胞瘤的潜在预后生物标志物和治疗靶点

大多数高危神经母细胞瘤患者对目前的治疗方案无效或复发,导致 5 年生存率低于 50%。这强调迫切需要确定新的治疗靶点。在这里,我们报告高 PIM 激酶表达与较差的总体存活率相关。用泛 PIM 抑制剂 AZD1208 或 PIM-447 处理神经母细胞瘤细胞系,通过抑制 mTOR 信号传导抑制增殖。在一组神经母细胞瘤细胞系中,我们观察到对 PIM 抑制的明显二元反应,表明特定的遗传病变控制对 PIM 抑制的反应。使用全基因组 CRISPR-Cas9 遗传筛选,我们确定 NF1 丢失是 PIM 激酶抑制剂的主要抗性机制。AZD1208 治疗会损害 NF1 野生型异种移植物的生长,而NF1敲除细胞不敏感。因此,我们的数据表明 PIM 抑制可能是 NF1 野生型神经母细胞瘤的一种新型靶向治疗。摩尔癌症治疗; 17(4); 849-57。©2018 AACR。
更新日期:2018-02-13
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