CDK7 inhibition suppresses aberrant hedgehog pathway and overcomes resistance to smoothened antagonists
CDK7 inhibition suppresses aberrant hedgehog pathway and overcomes resistance to smoothened antagonists
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CDK7 抑制可抑制异常的刺猬通路并克服对平滑拮抗剂的耐药性
DOI：
10.1073/pnas.1815780116
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发表时间：
2019-06-25
影响因子：
11.1
通讯作者：
Tang, Yujie
中科院分区：
文献类型：
--
作者：
Liu, Fang;Jiang, Wenyan;Tang, Yujie
意义FDA批准的抗刺猬药物用于治疗刺猬驱动的癌症，其作用是拮抗平滑的上游成分；然而，对平滑抑制物(SMOI)药物的耐药性已被描述。我们先前的研究表明，表观遗传或转录靶向治疗代表了一种能有效克服SMOI耐药性的抗刺猬治疗策略。在这里，我们报道通过靶向CDK7的转录抑制可以抑制异常的Hedgehog通路和Hedgehog驱动的癌症的生长，无论是对SMOI药物的反应还是耐药，支持CDK7抑制作为一种有前景的克服SMOI耐药性的治疗策略。由于多种CDK7靶向药物最近已进入肿瘤治疗的I期试验，我们的研究为在不久的将来将刺猬驱动的癌症纳入这些临床试验提供了临床前理论基础。异常的Hedgehog(HH)通路在多种癌症类型中起着重要作用，因此有望成为药物靶点。目前临床上可用的Hedgehog靶向药物大多通过拮抗上游组分平滑起作用；然而，FDA批准的平滑抑制剂(SMOI)药物的原始和获得性耐药已被描述。我们最近证明，BET抑制剂通过拮抗HH途径的核心转录因子GLI1和GLI2的转录，有效地抑制SMOI耐药的HH驱动的肿瘤，提示表观遗传或转录靶向治疗是一种可以克服SMOI耐药的抗HH治疗策略。在这里，我们对表观遗传或转录靶向小分子进行了无偏见的筛选，以测试它们对GLI1和GLI2转录的抑制作用或对HH驱动的肿瘤细胞系的细胞活力的抑制作用。THZ1，一种细胞周期蛋白依赖性激酶7(CDK7)的共价抑制剂，在我们的筛选中被确定为最受欢迎的药物。我们随后证实，无论是用小分子抑制剂还是CRISPR-Cas9途径拮抗CDK7，都会显著抑制GLI1和GLI2的转录，从而在体外和体内有效地抑制HH驱动的癌症。更重要的是，拮抗CDK7保留了对HH驱动的癌症的抑制活性，几乎所有迄今描述的原始或获得性SMOI耐药。此外，我们揭示了CDK7抑制和BET抑制在对抗异常的HH途径和对SMOI敏感或耐药的HH驱动的癌症方面的协同作用。我们的结果表明，通过靶向CDK7的转录抑制是治疗HH驱动的癌症的一种有前途的治疗策略，特别是那些对SMOI药物具有原始或获得性耐药性的癌症。
Significance There have been FDA-approved anti-hedgehog drugs for treating hedgehog-driven cancers, which act by antagonizing the upstream component smoothened; however, resistance to smoothened inhibitor (SMOi) drugs have been described. Our previous study demonstrates that epigenetic or transcriptional targeted therapy represents an anti-hedgehog therapeutic strategy that can effectively overcome SMOi resistance. Here we report that transcriptional inhibition through targeting CDK7 suppresses the aberrant hedgehog pathway and growth of hedgehog-driven cancers either responsive or resistant to SMOi drugs, supporting CDK7 inhibition as a promising therapeutic strategy for overcoming SMOi resistance. Since multiple CDK7-targeted drugs have recently entered phase I trial for tumor therapy, our study provides the preclinical rationale for enrolling hedgehog-driven cancers into those clinical trials in the near future. The aberrant hedgehog (Hh) pathway plays important roles in multiple cancer types, therefore serving as a promising drug target. Current clinically available hedgehog-targeted drugs act mostly by antagonizing the upstream component smoothened; however, both primary and acquired resistance to FDA-approved smoothened inhibitor (SMOi) drugs have been described. We have recently demonstrated that the BET inhibitor effectively suppresses SMOi-resistant Hh-driven cancers through antagonizing transcription of GLI1 and GLI2, the core transcriptional factors of Hh pathway, suggesting epigenetic or transcriptional targeted therapy represents an anti-Hh therapeutic strategy that can overcome SMOi resistance. Here we performed an unbiased screening of epigenetic or transcriptional targeted small molecules to test their inhibitory effects on GLI1 and GLI2 transcription or cell viability of Hh-driven tumor lines. THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), is identified as the top hit in our screening. We then confirmed that antagonizing CDK7 by either small-molecule inhibitors or the CRISPR-Cas9 approach causes substantial suppression of GLI1 and GLI2 transcription, resulting in effective inhibition of Hh-driven cancers in vitro and in vivo. More importantly, antagonizing CDK7 retains inhibitory activity against Hh-driven cancers with almost all so-far described primary or acquired SMOi resistance. Furthermore, we reveal a synergy between CDK7 inhibition and BET inhibition on antagonizing aberrant Hh pathway and Hh-driven cancers that are either responsive or resistant to SMOi. Our results illustrate transcriptional inhibition through targeting CDK7 as a promising therapeutic strategy for treating Hh-driven cancers, especially those with primary or acquired resistance to SMOi drugs.