MYCN-Amplified Neuroblastoma Is Addicted to Iron and Vulnerable to Inhibition of the System Xc-/Glutathione Axis.
MYCN-Amplified Neuroblastoma Is Addicted to Iron and Vulnerable to Inhibition of the System Xc-/Glutathione Axis.
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DOI：
10.1158/0008-5472.can-20-1641
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发表时间：
2021-04-01
期刊：
影响因子：
11.2
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中科院分区：
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MYCN在20-25%的神经母细胞瘤中扩增，MYCN扩增的神经母细胞瘤导致了很大比例的儿童癌症相关死亡。对这种亚型癌症的治疗改进是当务之急。在这里，我们发现了神经母细胞瘤中mycn依赖性的治疗易感性。也就是说，扩增的MYCN通过表达关键受体重新连接细胞，最终通过增加铁输入转铁蛋白受体1 （TfR1）的表达增强铁内流。积累的铁引起活性氧（ROS）的产生，mycn扩增的神经母细胞瘤通过增加该受体的转录，显示出对系统Xc-胱氨酸/谷氨酸反转运蛋白解毒的依赖性增强。这种依赖性使得用铁下垂诱导剂靶向系统Xc-/谷胱甘肽（GSH）途径具有明显的脆弱性。这种依赖性可以通过fda批准的类风湿性关节炎（RA）药物磺胺氮嗪（SAS）和金嘌呤治疗来利用：在mycn基因放大的患者来源的异种移植模型中，这两种疗法都可以阻断生长并诱导铁下垂。SAS和铁酰ofin的活性在很大程度上被铁磷酸酯抑制剂铁抑素-1、抗氧化剂如NAC或铁清除剂去铁胺（DFO）所减轻。DFO减少了金烷酮诱导的ROS，进一步将mycn扩增NB中铁捕获增加与诱导ROS药物的治疗易感性联系起来。这些数据揭示了由铁积累增加和随后对系统Xc-/GSH途径的依赖引起的癌基因易感性。
MYCN is amplified in 20–25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for this subtype of cancer is a high priority. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified MYCN rewired the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1 (TfR1). Accumulating iron caused reactive oxygen species (ROS) production, and MYCN-amplified neuroblastomas showed enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. This dependence created a marked vulnerability to targeting the system Xc-/glutathione (GSH) pathway with ferroptosis inducers. This reliance can be exploited through therapy with FDA-approved rheumatoid arthritis (RA) drugs sulfasalazine (SAS) and auranofin: in MYCN-amplified, patient-derived xenograft models, both therapies blocked growth and induced ferroptosis. SAS and auranofin activity was largely mitigated by the ferroptosis inhibitor ferrostatin-1, antioxidants like NAC, or by the iron scavenger deferoxamine (DFO). DFO reduced auranofin-induced ROS, further linking increased iron capture in MYCN-amplified NB to a therapeutic vulnerability to ROS-inducing drugs. These data uncover an oncogene vulnerability to ferroptosis caused by increased iron accumulation and subsequent reliance on the system Xc-/GSH pathway.