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Identifying metabolic dependencies in genetic subtypes of KRAS-driven lung cancer

识别 KRAS 驱动的肺癌遗传亚型的代谢依赖性

基本信息

批准号：
10352215
负责人：
Thales Papagiannakopoulos
金额：
$ 47.3万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-02 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10352215
关键词：
Address Antioxidants Biochemical Genetics Biochemical Pathway CRISPR/Cas technology Cancer Patient Cell Line Cells Clinical Clinical Oncology Clinical Trials Dependence Gene Expression Profile Genes Genetic Genetic Screening Genetic Transcription Genetically Engineered Mouse Genome engineering Genotype Glucose Glutaminase Glutamine Goals Homeostasis Human In Vitro K-ras mouse model KRAS2 gene Lead Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Metabolic Metabolic Pathway Metabolism Modeling Molecular Mus Mutation Non-Small-Cell Lung Carcinoma Nutrient Oncoproteins Outcome Oxidative Stress Pathway Pathway interactions Pharmacology Pre-Clinical Model Production Property Reactive Oxygen Species Research Resistance Resistance development Role Solid Neoplasm Stratification Technology Therapeutic base cancer cell cancer subtypes cancer type early phase clinical trial genetic approach in vivo inhibitor loss of function mutation mutant novel novel therapeutic intervention patient derived xenograft model patient stratification precision medicine preclinical study programs resistance mechanism response targeted treatment treatment responders tumor virtual

项目摘要

SUMMARY Treating KRAS mutant lung adenocarcinoma (LUAD) remains a major challenge for clinical oncology. Approximately 20% of KRAS mutant LUAD tumors carry loss-of-function mutations in KEAP1, a negative regulator of NRF2, which is the master transcriptional regulator of the endogenous antioxidant response. Using CRISPR/Cas9-based somatic editing in a genetically engineered mouse model of KRAS-driven LUAD we demonstrated that loss of Keap1 hyper- activates Nrf2 and dramatically accelerates KRAS-driven LUAD. Combining CRISPR/Cas9- based genetic screening and metabolic analyses, we showed that Keap1 mutant cells are dependent on increased glutamine metabolism, and this property can be therapeutically exploited through the pharmacological inhibition. In this application we focus on characterizing the molecular mechanisms and therapeutic potential of targeting glutamine metabolism in KRAS- driven KEAP1 mutant LUAD, and other cancers with hyperactivation of the NRF2 antioxidant pathway. This application aims to: 1) Assess the therapeutic potential of inhibiting glutamine utilization in both human and murine KRAS-driven LUAD models with KEAP1 mutations, 2) Characterize the metabolic mechanisms underlying glutamine dependency in KEAP1 mutant LUAD, and 3) Determine the therapeutic potential of inhibiting glutaminolysis in cancers with hyperactivation of the NRF2 pathway. Our studies will provide a rationale for sub-stratification of patients with hyperactivation of the NRF2 pathway as treatment responders to glutaminase inhibitors, which is pertinent to the goals of precision medicine. !

总结治疗KRAS突变型肺腺癌（LUAD）仍然是临床治疗的主要挑战。肿瘤学大约20%的KRAS突变型LUAD肿瘤携带功能丧失突变， KEAP 1是NRF 2的负调节因子，NRF 2是细胞的主要转录调节因子。内源性抗氧化反应使用基于CRISPR/Cas9的体细胞编辑在遗传学上 KRAS驱动的LUAD的工程小鼠模型，我们证明了Keap 1超表达的缺失，激活Nrf 2并显著加速KRAS驱动的LUAD。结合CRISPR/Cas9- 基于遗传筛选和代谢分析，我们发现Keap 1突变细胞是依赖于增加的谷氨酰胺代谢，并且这种性质可以是治疗性的。通过药理学抑制来利用。在本申请中，我们专注于表征目的探讨靶向谷氨酰胺代谢在KRAS- 驱动的KEAP 1突变体LUAD和其他具有NRF 2抗氧化剂过度活化的癌症通路本申请旨在：1）评估抑制谷氨酰胺的治疗潜力在具有KEAP 1突变的人和鼠KRAS驱动的LUAD模型中的利用，2）表征KEAP 1突变体中谷氨酰胺依赖性的代谢机制 LUAD，和3）确定在具有LUAD的癌症中抑制多巴胺分解的治疗潜力。 NRF 2通路的过度激活。我们的研究将提供一个基本原理， NRF 2通路过度活化的患者作为转氨酶治疗应答者抑制剂，这与精准医学的目标有关。 !