权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9294607
负责人：
Liron Bar-Peled
金额：
$ 11.48万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9294607
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 Dependency 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 Transduction Stress Technology Therapeutic Transcriptional Activation Up-Regulation Xenograft Model Zinc Fingers anti-cancer therapeutic beta catenin bropirimine cancer cell cell growth chemoproteomics in vivo inhibitor/antagonist knock-down lung xenograft next generation programs 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.

项目总结