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去调控和过表达的MYC来维持其生长和增殖，但对这种致癌转录因子的药理学抑制已被证明是令人生畏的。最近对MYC如何促进癌细胞状态的见解表明，通过它的致癌特性可以在治疗上加以利用。当过表达时，MYC充当转录的全局放大器，导致所有活跃转录基因的表达大量上调。此外，致癌MYC是由大的增强子区域，或超级增强子（SE），促进其高水平的表达，是非常敏感的扰动转录调控。鉴于致癌MYC作为SE相关转录放大器的新地位，我们试图选择性地靶向其转录调控机制。RNA聚合酶II的转录周期由一组细胞周期蛋白依赖性激酶（CDK）控制，包括CDK 7-13，在转录起始和延伸中起关键作用。我们假设，抑制CDK 7（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驱动的全局转录扩增，选择性地靶向MYC过表达的癌细胞。在初步研究中，我们证明了惊人的活性和选择性THZ 1，一种新的原型共价CDK 7抑制剂，在MYCN扩增的神经母细胞瘤（NB）细胞相比，那些没有MYCN扩增。这种效应与抑制全球MYCN依赖性转录扩增和优先减少SE相关基因的表达有关，特别是MYCN，对正常组织没有毒性。为了验证CDK 7抑制作为针对MYCN扩增的NB的易处理的治疗策略，我们现在解决三个关键的研究问题。目标1：具有改善的药代动力学的新THZ 1类似物与靶向或标准细胞毒性药物组合，是否会在MYCN扩增的NB中诱导持久的反应？目的2：MYCN扩增的NB细胞中CDK 7抑制的选择性致死性的基础是什么？目的3：THZ 1的耐药机制是什么？我们产生的结果预计将产生重要的见解，可用于抑制高风险NB中MYCN功能扩增的方法，因此可能为治疗MYC家族蛋白表达失调的其他癌症提供令人信服的理由，这代表了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.