CDK7介导的甲状腺未分化癌中转录成瘾的分子机制及其靶向治疗

ATC is the most malignant thyroid tumor without clear pathogenesis and effective treatment. Through drug screening and functional experiments in vitro and vivo, we found that THZ1, a novel inhibitor of kinase CDK7, can kill ATC cells efficiently and specifically. Clinical specimen analysis showed that CDK7 was highly expressed in patients with ATC, and the expression level was negatively correlated with survival time. Recent studies suggest that tumor progression and malignancy are closely related to abnormal gene transcription and targeting CDK7 dependent transcription addiction may be a new method for the treatment of malignant tumors. Based on analysis of epigenomics, we mapped the distribution map of the whole genome enhancers of ATC and found the unique Super-Enhancer and regulatory element of ATC. Combined with the whole genome expression profile analysis, the drug targets of THZ1 in ATC were identified. Our proposed work is to further explain the molecular mechanism of THZ1 on target regulation, at the same time we are to explore the role and mechanism of new target in the pathogenesis of ATC and the combined targeting therapy of THZ1 and other drugs. This study will help us to better understand the mechanism of CDK7-dependent transcriptional addiction in tumorigenesis and to find new drug targets for ATC treatment, providing a theoretical basis for the targeted therapy of ATC.

甲状腺未分化癌（ATC）是恶性程度最高的甲状腺肿瘤，发病机制不清，尚无有效的治疗手段。通过药物筛选和体内外功能学实验，我们发现激酶CDK7的新型抑制剂THZ1能高效特异性地杀伤ATC细胞。临床标本分析表明CDK7在ATC患者中高表达，其表达水平与患者生存时间呈负相关。进一步研究发现，ATC中存在CDK7依赖的转录成瘾，而其可能是靶向治疗ATC的新手段。通过表观组学分析，我们绘制了ATC全基因组增强子分布图谱，发现ATC特有的超级增强子和调控原件。通过联合全基因组表达谱分析，鉴定了THZ1在ATC中的药物靶点。拟进行的工作将进一步深入阐释THZ1对靶点调控的分子机制；探讨新靶点在ATC发病进程中的作用和机制；THZ1与其他药物的联合靶向治疗。此研究将有助于更好地理解CDK7依赖的转录成瘾在肿瘤发生中的作用机制，发现新的针对ATC治疗的药物靶点，为ATC的靶向治疗提供理论基础。

甲状腺未分化癌（anaplastic thyroid carcinoma，ATC）是恶性程度最高的甲状腺肿瘤，发病机制尚不明确，且无有效的治疗手段。课题组研究了超级增强子驱动的癌基因转录成瘾在ATC进展中的机制和功能，并确定用于ATC治疗的新药靶点。课题组通过进行高通量化学筛选以确定抑制ATC细胞生长的新药，确定了THZ1是一种有效的抗ATC化合物，它可有效抑制细胞周期蛋白依赖性激酶7（CDK7）活性。课题组使用细胞活力测定、菌落形成分析、细胞周期分析和动物研究等方法检测了THZ1对ATC进展的影响。课题组通过临床标本分析表明CDK7在ATC患者中高表达，其表达水平与患者生存时间呈负相关。通过表观组学分析，课题组绘制了ATC全基因组增强子分布图谱，发现ATC特有的超级增强子和调控原件。通过联合全基因组表达谱分析，鉴定了THZ1在ATC中的药物靶点。课题组发现了许多ATC的新型癌基因，包括PPP1R15A，SMG9和KLF2。PPP1R15A的表达水平与ATC组织样本中的CDK7的表达相关，且其高表达与ATC患者的临床预后不良有关。在治疗方面，抑制CDK7或PPP1R15A能够使ATC细胞对常规化学疗法敏感。此研究将有助于理解CDK7依赖的转录成瘾在肿瘤发生中的作用机制，发现新的针对ATC治疗的药物靶点，为ATC的靶向治疗提供理论基础。