Many cancer types are driven by oncogenic transcription factors that have been difficult to drug. Transcriptional inhibitors, however, may offer inroads into targeting these cancers. Through chemical genomics screening, we identified that Ewing sarcoma is a disease with preferential sensitivity to THZ1, a covalent small-molecule CDK7/12/13 inhibitor. The selective CDK12/13 inhibitor, THZ531, impairs DNA damage repair in an EWS/FLI-dependent manner, supporting a synthetic lethal relationship between response to THZ1/THZ531 and EWS/FLI expression. The combination of these molecules with PARP inhibitors showed striking synergy in cell viability and DNA damage assays in vitro and in multiple models of Ewing sarcoma, including a PDX, in vivo without hematopoietic toxicity.

中文翻译：

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EWS / FLI赋予肿瘤细胞合成致死性以抑制尤文氏肉瘤中CDK12的表达。

许多癌症类型是由难以药物治疗的致癌转录因子驱动的。但是，转录抑制剂可能会为靶向这些癌症提供帮助。通过化学基因组学筛选，我们确定了尤因肉瘤是对THZ1（一种共价小分子CDK7 / 12/13抑制剂）具有优先敏感性的疾病。选择性CDK12 / 13抑制剂THZ531以EWS / FLI依赖性方式损害DNA损伤修复，支持对THZ1 / THZ531和EWS / FLI表达的反应之间的合成致死关系。这些分子与PARP抑制剂的组合在体外以及在无造血毒性的体内尤因肉瘤（包括PDX）的多种模型中，在细胞活力和DNA损伤测定中显示出惊人的协同作用。