Targeted disruption of the YAP/TAZ/TEAD axis in pancreatic cancer

胰腺癌中 YAP/TAZ/TEAD 轴的靶向破坏

• 批准号: 10189799
• 负责人: Behnam Nabet
• 金额: $ 11.07万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189799
• 关键词: Address; Automobile Driving; Binding; Biological Models; Biology; Bypass; CRISPR screen; Career Transition Award; Cell Line; Cells; Chemicals; Clinical; Combined Modality Therapy; Complex; Computational Biology; Cysteine; Data; Dependence; Development; Disease; Drug resistance; Educational workshop; Enhancers; Evaluation; Gene Expression Profiling; Genetic; Genetic Transcription; Goals; Human Cell Line; Individual; Interdisciplinary Study; KRAS2 gene; KRASG12D; Laboratories; Laboratory Research; Lesion; Literature; MAP Kinase Gene; MEK inhibition; MEKs; Malignant Neoplasms; Malignant neoplasm of pancreas; Measurement; Modeling; Mutate; Nature; Oncogenes; Organoids; Pancreatic Ductal Adenocarcinoma; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Prognosis; Proteins; Publishing; Regimen; Regulator Genes; Resistance; Role; Signal Transduction; Specificity; Survival Rate; System; Technology; Therapeutic; Therapeutic Effect; Time; Transcription Coactivator; Work; base; career development; design; epigenomics; experimental study; genetic approach; genetic regulatory protein; genetic signature; genome-wide; improved; inhibitor/antagonist; innovation; innovative technologies; insight; meetings; mouse model; multicatalytic endopeptidase complex; mutant; novel; novel therapeutic intervention; pancreatic cancer model; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; paralogous gene; programs; protein degradation; resistance mechanism; response; response biomarker; small molecule; targeted agent; targeted treatment; tool; translational model; treatment strategy

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating form of pancreatic cancer with dismal patient outcome. KRAS, which is commonly mutated in PDAC, is a driving oncogene in this disease. However, development of approaches to target KRAS has proven challenging and inhibitors targeting signaling networks downstream of KRAS such as the MAPK pathway have largely failed as single agents. The overall goal of this proposal is to use innovative chemical strategies to identify combination regimens in PDAC, which are urgently needed to improve patient survival. Combining CRISPR screens and epigenomic profiling, I identified that the YAP/TAZ/TEAD axis is a critical transcriptional node required for the bypass survival program upon KRAS loss or MEK inhibition. This data and published literature support the importance of directly targeting the YAP/TAZ/TEAD axis in PDAC. However, current YAP/TAZ/TEAD inhibitors have poor potency and off-target effects and genetic strategies to study critical transcription regulators have limited utility due to delays between protein loss and experimental measurement. To overcome these limitations, I developed a versatile tag-based technology platform known as the degradation tag (dTAG) system to induce rapid degradation of any target protein in cell lines and mouse models. The dTAG system enables evaluation of target protein loss with a small molecule degrader in a time-scale that is not possible with genetic approaches, facilitating evaluations of mutant KRAS, YAP and TAZ. In addition, the Gray laboratory developed a selective small molecule covalent TEAD inhibitor to irreversibly inactivate aberrant YAP/TAZ/TEAD signaling. The work proposed in this application will leverage the dTAG technology platform and a covalent TEAD inhibitor to establish the role of YAP/TAZ/TEAD in coordinating bypass survival in PDAC. In Aim 1, in the absence of direct YAP or TAZ inhibitors, I will use the dTAG system to define the direct YAP and TAZ transcriptional signaling program that promotes survival upon modulation of KRAS signaling. These experiments will demonstrate the potential of chemical degradation of YAP and TAZ and identify novel targetable vulnerabilities. In Aim 2, I will use PDAC cell lines and patient-derived organoid models to evaluate the translational potential of covalent TEAD inhibition as a combination regimen with KRAS signaling disruption. Integrating chemical biology, genome-scale analyses, and translational models of PDAC, I expect that PDAC-specific therapeutic insights will emanate from this work. To achieve these aims, I designed a 3-year plan that includes participation in scientific and career development meetings, workshops and coursework to further develop my cancer chemical biology and computational biology expertise. This career transition award will greatly facilitate my goal of leading a multidisciplinary research laboratory focused on addressing challenges in the treatment of pancreatic cancer.

项目摘要/摘要 摘要胰腺导管腺癌(PDAC)是胰腺癌的一种破坏性形式，患者情绪低落。 结果。KRAS是PDAC中常见的突变基因，是本病的致癌基因。然而， 事实证明，针对KRAS的方法的开发具有挑战性，而针对信令网络的抑制因素 KRAS的下游，如MAPK途径，作为单一药物在很大程度上失败了。这个项目的总体目标是 建议在PDAC中使用创新的化学策略来确定联合方案，这是迫切需要的 需要提高患者的存活率。结合CRISPR筛查和表观基因组图谱，我鉴定了 YAP/TAZ/TEAD轴是KRAS丢失后旁路存活程序所需的关键转录节点 或MEK抑制。这些数据和发表的文献支持了直接针对 PDAC中的YAP/TAZ/TEAD轴。然而，目前的YAP/TAZ/TEAD抑制剂效力较差且偏离靶点 研究关键转录调控因子的效应和遗传策略由于两者之间的延迟而效用有限 蛋白质损失和实验测量。为了克服这些限制，我开发了一个通用的基于标记的 称为降解标签(DTag)系统的技术平台，可诱导任何目标的快速降解 细胞系和小鼠模型中的蛋白质。Dtag系统能够评估目标蛋白质的损失 分子在时间尺度上的降解，这是遗传方法所不可能的，有助于对突变的评估 KRAS、YAP和TAZ。此外，格雷实验室还开发了一种选择性小分子共价tead 抑制剂，不可逆转地失活异常的YAP/TAZ/TEAD信号。本申请中提出的工作将 利用Dtag技术平台和共价TEAD抑制剂确立YAP/TAZ/TEAD在 协调PDAC的旁路存活率。在目标1中，在没有直接YAP或TAZ抑制剂的情况下，我将使用 Dtag系统定义直接的YAP和TAZ转录信号程序，促进患者的生存 KRAS信号的调制。这些实验将证明YAP的化学降解潜力。 和TAZ，并识别新的可定向漏洞。在目标2中，我将使用PDAC细胞系和患者来源的 评估作为联合方案的共价TEAD抑制的翻译潜力的有机模型 KRAS信号中断。整合化学生物学、基因组规模分析和翻译模型 对于PDAC，我期望从这项工作中得出PDAC特有的治疗见解。为达致这些目标，我 设计了一个3年计划，其中包括参加科学和职业发展会议、研讨会和 进一步发展我的癌症化学生物学和计算生物学专业知识的课程。这份职业 过渡奖将极大地促进我的目标，即领导一个专注于 应对胰腺癌治疗中的挑战。