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

项目 3：针对非小细胞肺癌治疗耐药的转录机制。

• 批准号: 10231100
• 负责人: MATTHEW L. MEYERSON
• 金额: $ 34.82万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-11 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231100
• 关键词: Address; Animal Model; BRAF gene; Cancer Model; Cancer Patient; Cancer cell line; Cell Line; Cell Survival; Cell model; Chemistry; Clinical; Clonal Evolution; Complex; Cyclin-Dependent Kinase Gene; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; DNA Sequence Alteration; Data; Data Analyses; Dependence; Development; Drug Targeting; Drug resistance; ERBB2 gene; Enhancers; Enzymes; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Epigenetic Process; Exhibits; Fibroblast Growth Factor Receptors; Genetic; Genetic Transcription; Genetically Engineered Mouse; Genome; Goals; In Vitro; Individual; Informatics; KRAS2 gene; Lead; MEKs; Malignant Neoplasms; Malignant neoplasm of lung; Molecular; Mutation; Non-Small-Cell Lung Carcinoma; Outcome; Pathway interactions; Patient-Focused Outcomes; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Population; Process; Property; Protein Kinase; Proteins; Regulatory Element; Residual state; Resistance; Resistance development; Signal Transduction; Specificity; Structural Chemistry; Structure; Testing; Therapeutic; Time; Transcript; Transcription Elongation; Transcription Initiation; Transcription Process; cancer cell; cancer therapy; clinical translation; design; genetic approach; improved; improved outcome; in vivo; inhibitor/antagonist; kinase inhibitor; member; mouse model; multidisciplinary; mutant; novel; patient subsets; prevent; resistance mechanism; response; small molecule; structural biology; synergism; targeted agent; targeted cancer therapy; targeted treatment; therapeutic target; therapy resistant; tool; transcription factor; transcriptomics; treatment response; treatment strategy

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.

基因组靶向疗法的使用改善了治疗反应和临床结果 分子定义的非小细胞肺癌患者亚群。虽然对这些疗法的反应 往往是戏剧性的，它们很少能持久，并且非常需要改善其持续时间 反应并延迟或防止治疗抵抗。我们小组和其他人的研究表明 逃避靶向药物初始治疗的癌细胞的特性。对这些数据的分析有 揭示了转录和表观遗传适应是细胞生存的必要条件 面对靶向治疗。 通过与核心 A（化学）和核心 B（结构）合作，我们获得了初步数据表明 高阶细胞周期蛋白依赖性激酶 (CDK) 的抑制剂，这些酶在转录中发挥关键作用 起始和延伸，在多种 NSCLC 中与靶向激酶抑制剂显示出有效的协同作用 体外和体内模型。具体来说，我们已经鉴定出 THZ1，一种共价 CDK7/12 抑制剂，设计 由 Core A 负责人 Gray 博士开发，作为一种工具化合物，与 EGFR（项目 1）、MEK 抑制剂具有协同作用 （项目 2）以及基因选择的 NSCLC 模型中的 ALK、HER2、BRAF、FGFR 和 PI3K。在这个 项目中，我们将通过使用遗传基因来推进针对靶向治疗的转录适应的努力 定义负责治疗协同作用的关键 CDK/细胞周期蛋白基因的工具，并使用此信息 设计更具选择性的 CDK 抑制剂和选择性降解剂，具有更高的特异性和体内 与 THZ1 相比的药理学。此外，我们将使用转录和表观遗传分析来定义 靶向治疗和 CDK 抑制剂之间的协同治疗机制。该项目将 鉴于这种方法的广泛适用性和持续的开发努力，适合临床转化 临床使用的转录CDK抑制剂。