Project 3: Targeting transcriptional mechanisms of therapeutic resistance in non-small cell lung cancer.

基因靶向治疗的使用改善了治疗反应和临床结果 非小细胞肺癌患者的分子定义亚群。虽然对这些疗法的反应 通常是戏剧性的，它们很少持久，而且有必要显著地改善 应对，延迟或防止治疗耐药。我们小组和其他人的研究表明， 逃脱靶向制剂初步治疗的癌细胞的特性。对这些数据的分析已经 揭示转录和表观遗传适应是持续存在的细胞生存的必要条件 面对靶向治疗。 与核心A(化学)和核心B(结构)合作，我们已经获得了初步数据，表明 高阶细胞周期蛋白依赖性激酶(CDKs)的抑制剂，这些酶在转录过程中发挥关键作用 在不同的非小细胞肺癌阵列中，与靶向激酶抑制剂显示出强大的协同作用 体外和体内的模型。具体地说，我们已经确定了THZ1，一种设计的共价CDK7/12抑制剂 由Core A领导者Gray博士作为与EGFR抑制剂协同的工具化合物(项目1)，MEK (项目2)以及ALK、HER2、BRAF、FGFR和PI3K在遗传选择的NSCLC模型中的表达。在这 项目，我们将推进我们的努力，通过使用基因来定向转录适应靶向治疗 定义与治疗协同作用有关的关键CDK/细胞周期蛋白基因的工具，并利用这些信息 设计更具选择性的CDK抑制剂和选择性降解剂，提高特异性和体内活性 与THZ1比较的药理作用。此外，我们将使用转录和表观遗传学分析来定义 靶向治疗和CDK抑制剂之间的治疗协同作用机制。这个项目将是 考虑到这种方法的广泛适用性和正在进行的开发工作，可以进行临床翻译 临床使用的转录CDK抑制剂。

The use of genomically targeted therapies has improved treatment response and clinical outcomes for molecularly defined subsets of patients with non-small cell lung cancers. While responses to these therapies can often be dramatic, they are rarely durable, and there is a significant need to improve the duration of response and delay or prevent treatment resistance. Studies from our group and others have characterized the properties of cancer cells which escape initial treatment with a targeted agent. Analyses of these data have revealed transcriptional and epigenetic adaptation as a requirement for the survival of cells that persist in the face of targeted therapy. Working with Core A (Chemistry) and Core B (Structure), we have obtained Preliminary Data suggesting that inhibitors of higher-order cyclin dependent kinases (CDKs), enzymes which perform key roles in transcriptional initiation and elongation, display potent synergy with targeted kinase inhibitors in a diverse array of NSCLC models both in vitro and in vivo. Specifically, we have identified THZ1, a covalent CDK7/12 inhibitor designed by Core A leader Dr. Gray, as a tool compound which synergizes with inhibitors of EGFR (Project 1), MEK (Project 2) as well as ALK, HER2, BRAF, FGFR and PI3K in genetically selected NSCLC models. In this project, we will advance our efforts in targeting transcriptional adaptation to targeted therapies by using genetic tools to define the key CDK/cyclin genes responsible for therapeutic synergy and using this information to design more selective CDK inhibitors and selective degraders with improved specificity and in vivo pharmacology as compared to THZ1. Further, we will use transcriptional and epigenetic analysis to define the mechanisms governing therapeutic synergy among targeted therapies and CDK inhibitors. This project will be amenable to clinical translation given the broad applicability of this approach and ongoing efforts to develop transcriptional CDK inhibitors for clinical use.