CDK7抑制剂THZ1靶向胰腺癌转录成瘾的作用及机制研究

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high mortality. Lack of effective treatment makes novel therapeutic discovery an urgent demand in PDAC research. Epigenetic dysregulation plays an important role in human tumors including PDAC, providing new opportunities in the drug discovery against PDAC. By screening an epigenetic-related compound library, we identified THZ1, a covalent inhibitor of CDK7, as a promising candidate. Multiple PDAC cell lines and PDCs (Patient Derived Cancer cells) were used to validate the efficacy of THZ1 in vitro. In addition, human PDX models and animal models of PDAC were utilized for examining THZ1 efficacy in vivo. Mehcanistically , RNA-seq was performed in search of downstream genes of THZ1. Some PDAC cell lines are hypersensitive to THZ1, while others are tolerant, which prompt us to explore the molecular mechanism behind THZ1 insensitivity. This research deepens our understanding of pancreatic carcinogenesis, and possibly offer new therapy against PDAC.

胰腺导管腺癌是一种恶性程度极高的肿瘤，缺乏有效的药物治疗。表观调控异常是肿瘤细胞的重要特征，为肿瘤靶向治疗提供了新的选择。通过筛选靶向表观调控相关分子的化合物库，我们发现靶向转录成瘾的CDK7抑制剂THZ1，有效的抑制了胰腺肿瘤细胞的增殖，并在多种体外体内模型证实。THZ1的靶点CDK7在胰腺癌发生发展中的功能未见报道，拟从临床数据、动物模型和细胞水平阐明CDK7对胰腺癌的重要性。在机制方面，拟从RNA测序入手寻找THZ1作用的下游关键基因。部分胰腺癌细胞对THZ1不敏感，促使我们探索胰腺癌细胞对THZ1敏感性不同的分子机制。本研究不仅拓展了我们对胰腺癌发病机制的认识，还有望为胰腺癌的治疗提供新的选择，同时也为THZ1进入临床应用提供一定分子依据。

胰腺导管腺癌是一种恶性程度极高的肿瘤，缺乏有效的药物治疗。表观调控紊乱是肿瘤细胞的重要特征，由于参与表观调控的分子许多是酶蛋白，适宜成为药物开发的靶点，因此为肿瘤靶向治疗提供了新的选择。通过筛选靶向表观调控分子的化合物库，我们发现靶向转录成因的CDK7抑制剂THZ1，能有效抑制胰腺肿瘤细胞的增殖，并在多种体内体外模型证实。THZ1的靶点CDK7的功能，在胰腺癌中未见报道。我们利用细胞模型、动物模型和临床样本，证实部分胰腺癌高表达CDK7，其生长依赖CDK7所调控的转录成瘾。对于高表达CDK7的胰腺癌细胞，THZ1使肿瘤细胞的转录水平广泛地下调，尤其抑制了有丝分裂和NFκB相关的信号通路。对于低表达CDK7的胰腺癌细胞，对THZ1存在固有性耐受，同时我们也观察到，长期使用THZ1处理的肿瘤细胞会出现获得性THZ1耐受。通过对分子机制的探索，发现癌基因MYC参与调控了肿瘤细胞对THZ1的耐药性。我们的研究解释了胰腺肿瘤细胞中存在转录依赖的现象，通过小分子化合物THZ1，抑制调节转录的关键分子CDK7，可以达到抑制肿瘤细胞生长的目的，同时我们也系统阐述了THZ1抑制胰腺肿瘤细胞的分子机制，并初步探讨了胰腺对THZ1出现耐受性的可能，为胰腺癌的治疗提供了一个新的思路与方法。