Lurbinectedin Inactivates the Ewing Sarcoma Oncoprotein EWS-FLI1 by Redistributing It within the Nucleus
Lurbinectedin Inactivates the Ewing Sarcoma Oncoprotein EWS-FLI1 by Redistributing It within the Nucleus
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DOI：
10.1158/0008-5472.can-16-0568
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发表时间：
2016-11-15
期刊：
影响因子：
11.2
通讯作者：
Grohar, Patrick J.
中科院分区：
文献类型：
--
作者：
Harlow, Matt L.;Maloney, Nichole;Grohar, Patrick J.
迫切需要开发新的方法来利用小分子靶向致癌转录因子。尤文肉瘤就是这种需要的象征，因为它依赖于EWS-FLI1转录因子的持续活性来维持恶性表型。我们之前已经证明小分子Trabectein会干扰EWS-FLI1。在这里，我们报告了重要的机制进展和第二代抑制剂，以提供对EWS-FLI1治疗靶点的洞察。我们发现Trabectedin通过将细胞核内的蛋白质重新分配到核仁来功能失活EWS-FLI1。这种效应植根于EWSR1的野生型功能，损害了嵌合癌蛋白的N端一半，已知在紫外光损伤存在的情况下，嵌合癌蛋白在细胞核内也有类似的重新分布。第二代Trabectedin类似物Lurbinectedin(PM01183)导致EWS-FLI1的核重新分布，导致启动子、mRNA和蛋白表达水平的活性丧失。肿瘤异种移植研究证实了这种作用，与伊立替康联合使用后，这种作用增加，导致肿瘤消退，并用良性脂肪细胞取代尤文肉瘤细胞。Lurbinectedin和伊立替康联合治疗的最终结果是，仅仅治疗11天，EWS-FLI1活性就完全逆转，30%到70%的小鼠已建立的肿瘤被消除。我们的结果说明了针对尤文肉瘤中心致癌驱动因素的疾病特异性治疗的临床前安全性和有效性。
There is a great need to develop novel approaches to target oncogenic transcription factors with small molecules. Ewing sarcoma is emblematic of this need, as it depends on the continued activity of the EWS-FLI1 transcription factor to maintain the malignant phenotype. We have previously shown that the small molecule trabectedin interferes with EWS-FLI1. Here, we report important mechanistic advances and a second-generation inhibitor to provide insight into the therapeutic targeting of EWS-FLI1. We discovered that trabectedin functionally inactivated EWS-FLI1 by redistributing the protein within the nucleus to the nucleolus. This effect was rooted in the wild-type functions of the EWSR1, compromising the N-terminal half of the chimeric oncoprotein, which is known to be similarly redistributed within the nucleus in the presence of UV light damage. A second-generation trabectedin analogue lurbinectedin (PM01183) caused the same nuclear redistribution of EWS-FLI1, leading to a loss of activity at the promoter, mRNA, and protein levels of expression. Tumor xenograft studies confirmed this effect, and it was increased in combination with irinotecan, leading to tumor regression and replacement of Ewing sarcoma cells with benign fat cells. The net result of combined lurbinectedin and irinotecan treatment was a complete reversal of EWS-FLI1 activity and elimination of established tumors in 30% to 70% of mice after only 11 days of therapy. Our results illustrate the preclinical safety and efficacy of a disease-specific therapy targeting the central oncogenic driver in Ewing sarcoma.