Ovarian cancer remains a significant cause of gynecologic cancer mortality, and novel therapeutic strategies are urgently needed in clinic as new treatment options. We previously showed that BET bromodomain inhibitors displayed promising efficacy for the treatment of epithelial ovarian cancer by downregulating pivot transcription factors. However, the potential antitumor activities and molecular mechanisms of other epigenetic or transcriptional therapies have not been systematically determined. Here, by performing an unbiased high-throughput drug screen to identify candidate compounds with antineoplastic effects, we identified THZ1, a recently developed covalent CDK7 inhibitor, as a new transcription-targeting compound that exerted broad cytotoxicity against ovarian tumors. Mechanistically, CDK7 represented a previously unappreciated actionable vulnerability in ovarian cancer, and CDK7 inhibition led to a pronounced dysregulation of gene transcription, with a preferential repression of E2F-regulated genes and transcripts associated with super-enhancers. Our findings revealed the molecular underpinnings of THZ1 potency and established pharmaceutically targeting transcriptional addiction as a promising therapeutic strategy in aggressive ovarian cancer. Mol Cancer Ther; 16(9); 1739–50. ©2017 AACR .

中文翻译：

---

靶向CDK7依赖的转录成瘾在卵巢癌中的临床前功效和分子机制

卵巢癌仍然是导致妇科癌症死亡的重要原因，临床上迫切需要新的治疗策略作为新的治疗选择。我们以前表明，BET bromodomain抑制剂通过下调枢轴转录因子显示出有希望的治疗上皮性卵巢癌的功效。但是，尚未系统确定其他表观遗传或转录疗法的潜在抗肿瘤活性和分子机制。在这里，通过进行无偏倚的高通量药物筛选以鉴定具有抗肿瘤作用的候选化合物，我们将THZ1（一种新近开发的共价CDK7抑制剂）鉴定为一种新型的靶向转录的化合物，对卵巢肿瘤具有广泛的细胞毒性。机械上，CDK7代表了卵巢癌中以前未曾意识到的可操作性脆弱性，而CDK7的抑制导致基因转录的明显失调，并优先抑制了E2F调控的基因和与超级增强子相关的转录本。我们的发现揭示了THZ1效能的分子基础，并确立了靶向转录成瘾的药学目标作为积极的卵巢癌的有前途的治疗策略。分子癌疗法；16（9）; 1739–50。©2017 AACR。我们的发现揭示了THZ1效能的分子基础，并确立了靶向转录成瘾的药学目标作为积极的卵巢癌的有前途的治疗策略。分子癌疗法；16（9）; 1739–50。©2017 AACR。我们的发现揭示了THZ1效能的分子基础，并确立了靶向转录成瘾的药学目标作为积极的卵巢癌的有前途的治疗策略。分子癌疗法；16（9）; 1739–50。©2017 AACR。