Targeting antioxidant vulnerabilities in KEAP1/NRF2 mutant NSCLC

针对 KEAP1/NRF2 突变 NSCLC 中的抗氧化脆弱性

• 批准号: 10428798
• 负责人: Chang JIANG
• 金额: $ 11.34万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10428798
• 关键词: Affect; Anabolism; Antioxidants; Biology; Cancer Center; Cell Death; Chronic; Complex; Critical Pathways; Cytosol; Data; Defect; Dependence; Development Plans; Disulfides; Drug Metabolic Detoxication; Electron Transport; Environment; Enzymes; Equilibrium; Genes; Glutathione; Goals; Homeostasis; Incentives; Journals; Knowledge; Laboratory Research; Lipid Peroxides; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Mentors; Mitochondria; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Oxidoreductase; Pathogenicity; Pathway interactions; Patients; Peer Review; Play; Positioning Attribute; Production; Proteins; Publishing; Radiation therapy; Reactive Oxygen Species; Research; Resistance; Role; Selenium; Signal Transduction; Somatic Mutation; Sulfhydryl Compounds; System; TXN gene; Therapeutic; Training; Transcriptional Regulation; Translations; Up-Regulation; antioxidant enzyme; base; career development; design; dietary manipulation; dithiol; effective therapy; glutathione peroxidase; in vivo; lung cancer cell; mutant; novel; oxidation; programs; selenoprotein; targeted treatment; therapeutic target; thioredoxin reductase; transcription factor; uptake

The transcription factor NRF2 is a central regulator of cellular redox balance. Mutations in NRF2 and its negative regulator KEAP1 are found in 15-34% of non-small cell lung cancer (NSCLC). The result of these mutations is constitutive NRF2 activation and chronic induction of a battery of NRF2 target genes, which confers resistance to chemo/radiation therapy. While targeting NRF2 holds great therapeutic potential, there is no effective strategy to inhibit the consequences of pathogenic KEAP1/NRF2 signaling. It is therefore critical to identify and understand vulnerabilities of KEAP1/NRF2 mutant NSCLC to develop effective therapies for patients harboring these mutations. NRF2 controls the transcription of many antioxidant enzymes, thereby regulating the detoxification of reactive oxygen species. However, it remains largely unknown which specific antioxidant enzymes can be therapeutically targeted to reverse the profound resistance of NRF2/KEAP1 mutations to oxidative stress, the key mediator of chemo/radiation therapy. Glutathione (GSH)/GSH reductase (GSR) and thioredoxin (TXN)/thioredoxin reductase (TXNRD) are two parallel, compensating thiol-dependent antioxidant pathways that critically regulate and maintain cellular thiol redox homeostasis and protein dithiol/disulfide balance. My preliminary results indicate that both GSR and TXNRD1 are strongly induced by NRF2 activation and contribute to the intrinsic resistance to the pro-oxidant therapies. However, they play unique roles in different cellular compartments. Specifically, NRF2 induced GSR acts to protect mitochondria from oxidation, while TXNRD1 protects the cytosol. Further, TXNRD1 upregulation is associated with the suppression of other selenoproteins, suggesting that NRF2 activation causes an imbalance in selenium distribution. Given the key role of selenoprotein in redox biology, the switch in the production of the different selenoproteins induced by NRF2 activation may create novel vulnerabilities of NRF2 active NSCLC with therapeutic potential. This proposal is designed to further strengthen these observations by defining the mechanistic basis of how GSR contributes to NRF2-mediated resistance to oxidative stress, and to leverage the imbalanced selenoprotein translation to develop potent therapeutic strategies for KEAP1/NRF2 mutant NSCLC. The following specific aims are pursued in this application: Aim 1. Investigate the role of GSR in NRF2-mediated resistance to oxidative stress. Aim 2. Define the role of NRF2 as a modulator of the selenoproteome in NSCLC. The knowledge and scientific expertise that I acquire from these proposed studies will facilitate my transition to an independent position. My long-term goal is to study the antioxidant enzymes in cancer, with a major focus on selenoproteins. In addition to the scientific goal, I have outlined a detailed career development plan to obtain skillsets that are key for leading a research laboratory and establishing a strong research program. I will conduct the proposed research and carry out the training plan under the guidance of my mentoring committee. I will embark on the excellent academic environment provided by Moffitt Cancer Center to achieve these goals and transition to an independent position.

转录因子 NRF2 是细胞氧化还原平衡的核心调节因子。 NRF2 突变及其阴性 调节因子 KEAP1 存在于 15-34% 的非小细胞肺癌 (NSCLC) 中。这些突变的结果是 NRF2 的组成型激活和一系列 NRF2 靶基因的慢性诱导，从而赋予抗性 化疗/放射治疗。虽然靶向 NRF2 具有巨大的治疗潜力，但尚无有效的策略 抑制致病性 KEAP1/NRF2 信号传导的后果。因此，识别和识别至关重要 了解 KEAP1/NRF2 突变 NSCLC 的脆弱性，为携带该突变的患者开发有效的治疗方法 这些突变。 NRF2 控制许多抗氧化酶的转录，从而调节 活性氧的解毒。然而，究竟哪种特定的抗氧化剂仍然很大程度上未知 酶可以作为治疗靶点来逆转 NRF2/KEAP1 突变的深度耐药性 氧化应激，化学/放射治疗的关键介质。谷胱甘肽 (GSH)/谷胱甘肽还原酶 (GSR) 和 硫氧还蛋白 (TXN)/硫氧还蛋白还原酶 (TXNRD) 是两个平行的、补偿性硫醇依赖性抗氧化剂 关键调节和维持细胞硫醇氧化还原稳态和蛋白质二硫醇/二硫化物的途径 平衡。我的初步结果表明 GSR 和 TXNRD1 均受到 NRF2 激活的强烈诱导 并有助于对促氧化疗法的内在抵抗。但他们却在不同的领域扮演着独特的角色 细胞室。具体来说，NRF2 诱导的 GSR 可以保护线粒体免受氧化，同时 TXNRD1 保护细胞质。此外，TXNRD1 上调与其他抑制作用相关。 硒蛋白，表明 NRF2 激活导致硒分布不平衡。给定密钥 硒蛋白在氧化还原生物学中的作用，由不同的硒蛋白诱导产生的开关 NRF2 激活可能会产生具有治疗潜力的 NRF2 活性 NSCLC 的新弱点。这个提议 旨在通过定义 GSR 如何贡献的机制基础来进一步加强这些观察结果 NRF2 介导的氧化应激抵抗力，并利用不平衡的硒蛋白翻译 开发针对 KEAP1/NRF2 突变 NSCLC 的有效治疗策略。追求以下具体目标 在本应用中： 目标 1. 研究 GSR 在 NRF2 介导的氧化应激抵抗中的作用。目标2。 定义 NRF2 作为 NSCLC 中硒蛋白组调节剂的作用。知识和科学专业知识 我从这些拟议的研究中获得的知识将有助于我过渡到独立职位。我的长期 目标是研究癌症中的抗氧化酶，主要关注硒蛋白。除了 为了实现科学目标，我制定了一份详细的职业发展计划，以获得领导科学事业的关键技能。 研究实验室并建立强大的研究计划。我将进行拟议的研究并进行 在导师委员会的指导下制定培训计划。我将踏上优秀的学术之路 莫菲特癌症中心提供的环境来实现这些目标并过渡到独立职位。