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

摘要 治疗KRAS突变型肺腺癌(LUAD)仍是临床面临的主要挑战 肿瘤学。大约20%的KRAS突变LUAD肿瘤携带功能丧失突变 Keap1是NRF2的负调控因子，NRF2是NRF2的主要转录调控因子 内源性抗氧化反应。基于CRISPR/CAS9的体细胞编辑在基因工程中的应用 KRAS驱动的LUAD的工程化小鼠模型我们证明了Keap1高表达缺失 激活Nrf2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Keap1突变细胞是 依赖于谷氨酰胺代谢的增加，这种特性可以在治疗上 通过药理抑制来利用。在本应用程序中，我们重点描述 靶向谷氨酰胺代谢的KRAS的分子机制和治疗潜力 驱动Keap1突变的LUAD和其他NRF2抗氧化剂过度激活的癌症 路径。该应用旨在：1)评估抑制谷氨酰胺的治疗潜力 在人和小鼠KRAS驱动的Keap1突变的LUAD模型中的应用，2) Keap1突变型谷氨酰胺依赖的代谢机制 LUAD，以及3)确定抑制癌症谷氨酰胺分解的治疗潜力 NRF2途径的过度激活。我们的研究将为亚层化提供理论基础 作为谷氨酰胺酶治疗反应者的NRF2通路过度激活患者 抑制剂，这与精准医学的目标有关。 好了！

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. !