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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：
10784801
负责人：
Thales Papagiannakopoulos
金额：
$ 46.36万
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 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10784801
关键词：
Acceleration Address Antioxidants Biochemical 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 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 Pre-Clinical Model Production Property Reactive Oxygen Species Research Resistance Resistance development Role Solid Neoplasm Stratification Technology Therapeutic 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 pharmacologic 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. !

概括治疗 KRAS 突变肺腺癌（LUAD）仍然是临床的主要挑战肿瘤学。大约 20% 的 KRAS 突变 LUAD 肿瘤携带功能丧失突变 KEAP1，NRF2 的负调节因子，NRF2 是内源性抗氧化反应。在基因编辑中使用基于 CRISPR/Cas9 的体细胞编辑在 KRAS 驱动的 LUAD 工程小鼠模型中，我们证明了 Keap1 的丢失激活 Nrf2 并显着加速 KRAS 驱动的 LUAD。结合 CRISPR/Cas9- 基于遗传筛选和代谢分析，我们发现 Keap1 突变细胞依赖于增加的谷氨酰胺代谢，这种特性可以用于治疗通过药理抑制来利用。在此应用中，我们重点关注表征 KRAS-中靶向谷氨酰胺代谢的分子机制和治疗潜力驱动 KEAP1 突变体 LUAD 和其他具有 NRF2 抗氧化剂过度激活的癌症途径。本申请旨在： 1) 评估抑制谷氨酰胺的治疗潜力在具有 KEAP1 突变的人类和小鼠 KRAS 驱动的 LUAD 模型中的利用，2) 表征 KEAP1 突变体中谷氨酰胺依赖性的代谢机制 LUAD，以及 3) 确定抑制谷氨酰胺分解在癌症中的治疗潜力 NRF2 通路的过度激活。我们的研究将为 NRF2 通路过度激活的患者对谷氨酰胺酶治疗有反应抑制剂，这与精准医学的目标相关。！