Transcriptional CDKs as therapeutic targets in MYC-dependent cancers

 描述(由申请人提供)：许多人类癌症依赖于解除调控和过度表达的MYC来持续生长和增殖，但事实证明，对这种致癌转录因子的药物抑制令人望而生畏。最近对MYC如何促进癌细胞状态的洞察表明，可以通过一种途径，将其致癌特性用于治疗。当过度表达时，MYC充当转录的全局放大器，导致所有活跃转录的基因大量上调表达。此外，致癌的MYC在转录上受到大的增强子区域或超级增强子(Ses)的调控，这些区域促进了MYC的高水平表达，并且对干扰非常敏感。鉴于致癌MYC作为SE相关转录放大器的新地位，我们试图选择性地针对控制其转录调控的机制。RNA聚合酶II的转录周期由一组细胞周期蛋白依赖性蛋白激酶(CDKs)控制，包括CDKs7-13，它们在转录起始和延伸过程中起着关键作用。我们假设，抑制CDK7，一种在转录调控中起主要作用的CDK，通过干扰基因转录的增强子-启动子控制，从而干扰MYC驱动的整体转录放大，选择性地针对MYC过表达的癌细胞。在初步研究中，我们展示了一种新的共价CDK7抑制剂原型THZ1在MYCN扩增的神经母细胞瘤(NB)细胞中的显著活性和选择性。这种作用与抑制全球MYCN依赖的转录扩增和优先降低SE相关基因的表达有关，尤其是MYCN，对正常组织没有毒性。为了验证CDK7抑制作为一种易操作的治疗策略来对抗MYCN扩增的NB，我们现在解决三个关键的研究问题。目的1：具有改进的药代动力学的较新的THZ1类似物，结合靶向或标准的细胞毒药，是否会在MYCN扩增的NB中诱导持久的反应？目的2：抑制CDK7对MYCN扩增的NB细胞选择性致死的依据是什么？目的3：THZ1耐药的机制是什么？我们产生的结果有望为抑制高危NB中放大的MYCN功能的方法提供重要的见解，因此可能为解除MYC家族蛋白表达的其他癌症的治疗提供令人信服的理论基础，这是我们研究的长期目标。

 DESCRIPTION (provided by applicant): Many human cancers depend on deregulated and overexpressed MYC for their sustained growth and proliferation, yet pharmacological inhibition of this oncogenic transcription factor has proved daunting. Recent insights into how MYC promotes the cancer cell state suggests an avenue through which its oncogenic properties could be exploited therapeutically. When overexpressed, MYC acts as a global amplifier of transcription, leading to massively upregulated expression of all actively transcribed genes. Moreover, oncogenic MYC is transcriptionally regulated by large enhancer regions, or super-enhancers (SEs), that facilitate its high-level expression and are acutely sensitive to perturbation. Given the emerging status of oncogenic MYC as a SE-associated transcriptional amplifier, we sought to selectively target the mechanisms governing its transcriptional regulation. The transcription cycle of RNA polymerase II is governed by a group of cyclin-dependent kinases (CDKs), including CDKs 7-13, with critical roles in transcription initiation and elongation. We hypothesize that inhibition of CDK7, a CDK with primary roles in transcription regulation, selectively targets MYC-overexpressing cancer cells by interfering with enhancer-promoter control of gene transcription and thus MYC-driven global transcriptional amplification. In preliminary studies, we demonstrated striking activity and selectivity by THZ1, a novel prototype covalent CDK7 inhibitor, in MYCN-amplified neuroblastoma (NB) cells compared to those without MYCN amplification. This effect was associated with inhibition of global MYCN-dependent transcriptional amplification and preferentially reduced expression of SE-associated genes, especially MYCN, without toxicity to normal tissues. To validate CDK7 inhibition as a tractable therapeutic strategy against MYCN-amplified NB, we now address three pivotal research questions. Aim 1: Will newer THZ1 analogs with improved pharmacokinetics, in combination with targeted or standard cytotoxic agents, induce durable responses in MYCN-amplified NB? Aim 2: What is the basis for the selective lethality of CDK7 inhibition in MYCN-amplified NB cells? Aim 3: What are the mechanisms of resistance to THZ1? The results we generate are expected to yield important insights into approaches that could be used to inhibit amplified MYCN function in high-risk NB, and therefore may provide a compelling rationale for the treatment of other cancers with deregulated expression of MYC family proteins, which represents the long-term goal of our research.