Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Mol Cancer Ther. 2018 Apr;17(4):849-857. doi: 10.1158/1535-7163.MCT-17-0868. Epub 2018 Feb 13.
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 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. .
大多数高危神经母细胞瘤患者对当前的治疗方案产生耐药性或复发，导致 5 年生存率低于 50%。这强调了迫切需要确定新的治疗靶点。在这里，我们报告高激酶表达与总体生存率降低相关。用泛 PIM 抑制剂 AZD1208 或 PIM-447 处理神经母细胞瘤细胞系可通过抑制 mTOR 信号来抑制增殖。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，这表明特定的遗传病变控制对 PIM 抑制的反应。通过使用全基因组 CRISPR-Cas9 基因敲除筛选，我们发现 NF1 缺失是 PIM 激酶抑制剂的主要耐药机制。用 AZD1208 处理会损害 NF1 野生型异种移植物的生长，而 NF1 敲除细胞则不敏感。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的靶向治疗方法。
