EWS/FLI is the defining mutation of Ewing sarcoma. This oncogene drives malignant transformation and progression and occurs in a genetic background characterized by few other recurrent cooperating mutations. In addition, the tumor is absolutely dependent on the continued expression of EWS/FLI to maintain the malignant phenotype. However, EWS/FLI is a transcription factor and therefore a challenging drug target. The difficulty of directly targeting EWS/FLI stems from unique features of this fusion protein as well as the network of interacting proteins required to execute the transcriptional program. This network includes interacting proteins as well as upstream and downstream effectors that together reprogram the epigenome and transcriptome. While the vast number of proteins involved in this process challenge the development of a highly specific inhibitors, they also yield numerous therapeutic opportunities. In this report, we will review how this vast EWS-FLI transcriptional network has been exploited over the last two decades to identify compounds that directly target EWS/FLI and/or associated vulnerabilities.

EWS/FLI 是尤文肉瘤的定义突变。该癌基因驱动恶性转化和进展，并且发生在以很少其他复发性合作突变为特征的遗传背景中。此外，肿瘤完全依赖于 EWS/FLI 的持续表达来维持恶性表型。然而，EWS/FLI 是一种转录因子，因此是一个具有挑战性的药物靶点。直接针对 EWS/FLI 的困难源于这种融合蛋白的独特特征以及执行转录程序所需的相互作用蛋白网络。该网络包括相互作用的蛋白质以及上游和下游效应器，它们一起重新编程表观基因组和转录组。虽然该过程中涉及的大量蛋白质挑战了高度特异性抑制剂的开发，但它们也产生了许多治疗机会。在本报告中，我们将回顾过去二十年如何利用这个庞大的 EWS-FLI 转录网络来识别直接针对 EWS/FLI 和/或相关漏洞的化合物。