EWS/FLI 使 CDK12 抑制在尤文肉瘤中具有肿瘤细胞合成致死性。
EWS/FLI Confers Tumor Cell Synthetic Lethality to CDK12 Inhibition in Ewing Sarcoma.
机构信息
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, 450 Brookline Avenue, Boston, MA 02215, USA; Ludwig Maximilians University of Munich, Munich 80539, Germany.
出版信息
Cancer Cell. 2018 Feb 12;33(2):202-216.e6. doi: 10.1016/j.ccell.2017.12.009. Epub 2018 Jan 18.
Abstract
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.
摘要
许多癌症类型受致癌转录因子驱动，这些转录因子难以用药物治疗。然而，转录抑制剂可能为靶向这些癌症提供途径。通过化学基因组学筛选，我们发现尤文肉瘤对 THZ1（一种共价小分子 CDK7/12/13 抑制剂）具有优先敏感性。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 的反应与 EWS/FLI 表达之间的合成致死关系。这些分子与 PARP 抑制剂的组合在体外和包括 PDX 在内的多种尤文肉瘤模型中在细胞活力和 DNA 损伤测定中表现出显著的协同作用，而没有造血毒性。
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