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Mapping druggable co-dependency pathways in NRF2-driven lung cancers

绘制 NRF2 驱动的肺癌的药物共依赖性途径

基本信息

批准号：
9891966
负责人：
Liron Bar-Peled
金额：
$ 22.88万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891966
关键词：
Address Advanced Malignant Neoplasm Anchorage-Independent Growth Antioxidants Applications Grants Binding Biochemical Biochemical Pathway Biological Biology Cancer Cell Growth Cancer Model Cancer Patient Cancer cell line Cell Proliferation Cells Chemicals Clustered Regularly Interspaced Short Palindromic Repeats Complex Cysteine Dependence Disease Doxycycline Drug Metabolic Detoxication Drug Targeting Environment Equilibrium Family Foundations Gene Expression Genes Genetic Genetic Transcription Goals Growth Lead Left Libraries Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Maps Mediating Metabolic Metabolic Pathway Methods Mus Mutation NR0B1 gene Non-Small-Cell Lung Carcinoma Nuclear Orphan Receptor Oncogenic Orphan Output Oxidation-Reduction Pathway interactions Patients Pharmacology Proliferating Protein Binding Domain Proteins Proteomics Reactive Oxygen Species Research Role Signal Pathway Signal Transduction Stress Technology Therapeutic Transcriptional Activation Up-Regulation Xenograft Model Zinc Fingers anti-cancer therapeutic beta catenin bropirimine cancer cell cell growth chemoproteomics druggable target in vivo inhibitor/antagonist knock-down lung xenograft next generation programs protein function protein protein interaction receptor response small molecule small molecule inhibitor targeted agent tool transcription factor tumor tumor xenograft tumorigenesis

项目摘要

Project Summary Rapidly proliferating cancer cells generate reactive oxygen species (ROS) that if left unchecked inhibit cell growth. To counter this stress, cancer cells and in particular non small cell lung cancers (NSCLC) rely on the activation of the NRF2 transcription factor, leading to the massive upregulation of key metabolic and detoxification proteins needed to restore redox balance. While directly targeting NRF2 with chemical inhibitors is challenging, we hypothesized that hyperactivation of this pathway would lead to an alteration of specific signaling and metabolic pathways required for the proliferation of these cells (co-dependencies), which themselves could be inhibited with small molecules. To identify these co-dependencies in NSCLC, we enriched for proteins containing reactive cysteines, which can be used as a chemical handle to develop inhibitors. This chemical proteomics screen identified hundreds of reactive cysteines regulated by NRF2, including a cryptic cysteine (C274) in the orphan receptor NR0B1. NR0B1 expression is severely restricted to those NCSLC cells and patient tumors with deregulated NRF2 signaling, where it functions as part of multimeric transcriptional complex to support the NRF2 gene expression program. As C274 in NR0B1 is necessary for NR0B1-complex formation, we exploited this residue to develop a small molecule inhibitor that covalently binds to it, subsequently disrupting the protein-protein interactions of NR0B1 and blocking the growth of NRF2-dependent cells, but not NRF2-independent cells. Thus, we have revealed NR0B1 as a druggable co-dependency of the NRF2 pathway. In this grant application, we build on our research on NR0B1 and further identify co-dependent pathways with NRF2 that can be pharmacologically interrogated. Using a powerful chemoproteomic framework, we will comprehensively define NRF2 co-dependencies by: 1) mapping the landscape of cysteine reactivity regulated by NRF2 in lung xenograft models, allowing us to identify cysteines on key proteins in the NRF2 pathway, which may become targetable opportunities in vivo 2) undertaking a small molecule screen to identify compounds that selectively inhibit the proliferation of NRF2-dependent NSCLC cell lines. Importantly, integrating a chemoproteomic platform into this screen, will allow for the rapid identification of co-dependent proteins, offering an unparalleled map of druggable NRF2 co-dependencies. The research proposed herein, takes full advantage of advanced cancer models and chemoproteomic technologies to reveal pharmacologically tractable proteins which are needed for the proliferation of NRF2-addicted cells and may provide a generalizable platform for inhibiting genetically defined cancers. These studies will not only provide a comprehensive understanding of NRF2 biology but might also lay the foundation for translational therapeutics benefiting lung cancer patients with deregulated NRF2 signaling.

项目摘要快速增殖的癌细胞产生活性氧（ROS），如果不加以抑制，为了对抗这种压力，癌细胞，特别是非小细胞肺癌（NSCLC）依赖于肿瘤细胞的生长。 NRF 2转录因子的激活，导致关键代谢和解毒蛋白需要恢复氧化还原平衡。而直接针对NRF 2与化学抑制剂是具有挑战性的，我们假设这一途径的过度激活将导致特异性的改变。这些细胞增殖所需的信号传导和代谢途径（共刺激依赖性），为了鉴定NSCLC中的这些共代谢依赖性，我们富集了对于含有反应性半胱氨酸的蛋白质，其可用作开发抑制剂的化学手柄。化学蛋白质组学筛选确定了数百个受NRF 2调控的活性半胱氨酸，包括一个隐蔽的孤儿受体NR 0 B1中的半胱氨酸（C274）。NR 0 B1的表达严格限于那些NCSLC细胞和具有失调的NRF 2信号传导的患者肿瘤，其中它作为多聚体转录因子的一部分起作用。由于NR 0 B1中的C274对于NR 0 B1-NRF 2复合物是必需的，我们利用这个残基开发了一种与之共价结合的小分子抑制剂，随后破坏NR 0 B1的蛋白质-RNA蛋白质相互作用，并阻断NRF 2-RNA依赖性细胞的生长，因此，我们已经揭示了NR 0 B1作为一种可药物化的协同依赖性， NRF 2通路。在这项基金申请中，我们建立在我们对NR 0 B1的研究基础上，进一步鉴定了依赖于NRF 2的蛋白质。使用强大的化学蛋白质组学方法，框架，我们将全面定义NRF 2的协同依赖性：1）绘制半胱氨酸的景观在肺异种移植模型中由NRF 2调节的反应性，使我们能够鉴定肺移植模型中关键蛋白质上的半胱氨酸。 NRF 2途径，这可能成为体内靶向机会2）进行小分子筛选，鉴定选择性抑制NRF 2-β 2依赖性NSCLC细胞系增殖的化合物。重要的是，将化学蛋白质组学平台整合到该筛选中，将允许快速鉴定依赖于辅酶A的蛋白质，提供了一个无与伦比的可药物化的NRF 2共代谢依赖性的图谱。本文提出的研究，充分利用先进的癌症模型和化学蛋白质组学技术， NRF 2依赖性细胞增殖所需的易降解蛋白质，为抑制基因定义的癌症提供了一个可推广的平台。这些研究不仅将提供一个对NRF 2生物学的全面理解，但也可能为转化治疗奠定基础通过解除NRF 2信号传导调节使肺癌患者受益。