Upregulation of the Mevalonate Pathway through EWSR1-FLI1/EGR2 Regulatory Axis Confers Ewing Cells Exquisite Sensitivity to Statins.
Upregulation of the Mevalonate Pathway through EWSR1-FLI1/EGR2 Regulatory Axis Confers Ewing Cells Exquisite Sensitivity to Statins.
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该项目的目的是寻找尤文肉瘤的新依赖性，尤文肉瘤是一种致命的疾病，迫切需要新的治疗方法。进行了非专利批准药物（FDA机构）的药理学筛选和EGFR 2下游靶点的研究。这两种方法显示MVA途径是尤文肉瘤的主要依赖性，而抑制该途径的他汀类药物是治疗尤文肉瘤的潜在新治疗剂。尤文肉瘤（EwS）是一种侵袭性原发性骨癌的儿童和年轻人的特点是致癌基因之间的融合编码FET-RNA结合蛋白和ETS转录因子，最常见的融合是EWSR 1-FLI 1。我们表明，EGR 2，尤文易感基因和EWSR 1-FLI 1的一个重要的直接目标，直接调节编码甲羟戊酸（MVA）途径的关键酶的基因的转录。因此，尤文肉瘤是表达最高水平的甲羟戊酸途径基因的肿瘤之一。此外，全基因组筛选表明MVA途径基因构成尤文细胞的主要依赖性。因此，HMG-CoA还原酶（MVA途径的限速酶）的他汀类抑制剂在EwS中表现出细胞毒性。他汀类药物诱导增加的ROS和脂质过氧化水平，以及减少的异戊二烯化蛋白质，如小GTP蛋白的膜定位。这些代谢作用导致S期进展的动力学改变和细胞凋亡。他汀类药物诱导的效应可以通过MVA途径的下游产物来挽救。最后，我们进一步表明，他汀类药物损害肿瘤生长在不同的尤因PDX模型。总而言之，数据显示，他汀类药物，这是专利，耐受性良好，价格低廉的化合物，应强烈考虑在治疗武器库对这种致命的儿童疾病。
The objective of this project was to search for new dependencies in Ewing sarcoma, a deadly disease for which new therapeutic approaches are urgently needed. A pharmacological screening of off-patent approved drugs (FDA agency) and the investigation of downstream targets of EGR2 were performed. The two approaches showed the MVA pathway as a major dependency in Ewing sarcoma and statin, an inhibitor of this pathway, as a potential new therapeutic agent for the treatment of Ewing sarcoma. Ewing sarcoma (EwS) is an aggressive primary bone cancer in children and young adults characterized by oncogenic fusions between genes encoding FET-RNA-binding proteins and ETS transcription factors, the most frequent fusion being EWSR1-FLI1. We show that EGR2, an Ewing-susceptibility gene and an essential direct target of EWSR1-FLI1, directly regulates the transcription of genes encoding key enzymes of the mevalonate (MVA) pathway. Consequently, Ewing sarcoma is one of the tumors that expresses the highest levels of mevalonate pathway genes. Moreover, genome-wide screens indicate that MVA pathway genes constitute major dependencies of Ewing cells. Accordingly, the statin inhibitors of HMG-CoA-reductase, a rate-limiting enzyme of the MVA pathway, demonstrate cytotoxicity in EwS. Statins induce increased ROS and lipid peroxidation levels, as well as decreased membrane localization of prenylated proteins, such as small GTP proteins. These metabolic effects lead to an alteration in the dynamics of S-phase progression and to apoptosis. Statin-induced effects can be rescued by downstream products of the MVA pathway. Finally, we further show that statins impair tumor growth in different Ewing PDX models. Altogether, the data show that statins, which are off-patent, well-tolerated, and inexpensive compounds, should be strongly considered in the therapeutic arsenal against this deadly childhood disease.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
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影响因子：
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作者：
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通讯作者：
Delattre O
影响因子：
4.7
作者：
Agarwal, B;Halmos, B;Holt, PR
通讯作者：
Holt, PR
影响因子：
64.8
作者：
Gorthi A;Romero JC;Loranc E;Cao L;Lawrence LA;Goodale E;Iniguez AB;Bernard X;Masamsetti VP;Roston S;Lawlor ER;Toretsky JA;Stegmaier K;Lessnick SL;Chen Y;Bishop AJR
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