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Uncovering Genotype Specific Vulnerabilities in KRAS Mutant Lung Cancer?

发现 KRAS 突变肺癌的基因型特异性漏洞？

基本信息

批准号：
10224132
负责人：
Thales Papagiannakopoulos
金额：
$ 38.77万
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：
2018-09-03 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224132
关键词：
Address Affect Amino Acids Antioxidants Belief Bioenergetics CRISPR/Cas technology Cancer Patient Cells Citric Acid Cycle Clinical Oncology Cysteine Data Dependence Diet Genetic Genetic Screening Genetic Transcription Genetically Engineered Mouse Genome engineering Genotype Glucose Glutamates Glutaminase Glutamine Glutathione Glycine Goals Growth Human K-ras mouse model KRAS2 gene Lead Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Metabolic Metabolic Pathway Metabolism Modeling Mus Mutation Non-Essential Amino Acid Non-Small-Cell Lung Carcinoma Nutrient Oncoproteins Outcome Pathway interactions Phase I Clinical Trials Phosphoserine aminotransferase Production Proteins Research Role Serine Solid Neoplasm Source Stratification System Technology Therapeutic antiporter base cancer cell cost deprivation dietary genetic approach human model inhibitor/antagonist knock-down loss of function mutation mouse model mutant new therapeutic target novel novel therapeutic intervention nuclear factor-erythroid 2 nucleotide metabolism patient derived xenograft model patient stratification pre-clinical precision medicine preclinical study programs response targeted treatment therapeutic evaluation treatment responders tumor tumor progression uptake 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. Our data are in line with mounting evidence demonstrating that, contrary to popular belief, antioxidants can promote cancer progression. Combining CRISPR/Cas9-based genetic screening and metabolic analyses, we have identified novel synthetic lethal interactions in KEAP1 mutant cells. We observe that the ability of KEAP1 mutant tumors to divert their metabolism towards antioxidant production comes with a cost, creating metabolic vulnerabilities that may be targeted by novel therapeutic strategies. In preliminary studies, we observed a dependency of KEAP1 mutant tumors on the amino acid serine. In this application we focus on elucidating this newly appreciated metabolic vulnerability of KRAS-driven KEAP1 mutant tumors to serine and explore the therapeutic potential of targeting serine metabolism in highly relevant pre-clinical mouse and human models. This application aims to: 1) Determine the therapeutic potential of inhibiting the serine transporter SLC1A5 and serine uptake in KRAS-driven LUAD models with KEAP1 mutations, 2) Define the metabolic mechanisms underlying serine dependency in LUAD and other KEAP1 mutant cancers, 3) Determine whether dietary serine restriction can selectively affect the growth of KEAP1 mutant tumors, 4) Dissect the metabolic crosstalk of glutamine and serine dependency 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 therapies targeting serine metabolism, which is pertinent to the goals of precision medicine.

总结治疗KRAS突变型肺腺癌（LUAD）仍然是临床肿瘤学的主要挑战。大约20%的KRAS突变型LUAD肿瘤携带KEAP 1功能缺失突变，这是一种阴性表达。 NRF 2是内源性抗氧化反应的主要转录调节因子。使用在KRAS驱动的LUAD的基因工程小鼠模型中，基于CRISPR/Cas9的体细胞编辑研究表明，KEAP 1的缺失会过度激活NRF 2，并显著加速KRAS驱动的LUAD。我们数据与越来越多的证据相一致，这些证据表明，与流行的观点相反，抗氧化剂可以促进癌症进展。我们结合基于CRISPR/Cas9的遗传筛查和代谢分析，在KEAP 1突变细胞中发现了新的合成致死相互作用。我们观察到KEAP 1的能力突变肿瘤将其代谢转向抗氧化剂生产是有代价的，这些弱点可能是新的治疗策略的目标。在初步研究中，我们观察到 KEAP 1突变型肿瘤对氨基酸丝氨酸的依赖性。在本申请中，我们专注于阐明这一点。新认识的KRAS驱动的KEAP 1突变肿瘤对丝氨酸的代谢脆弱性，在高度相关的临床前小鼠和人类模型中靶向丝氨酸代谢的治疗潜力。本申请旨在：1）确定抑制丝氨酸转运蛋白SLC 1A 5和 KRAS驱动的具有KEAP 1突变的LUAD模型中的丝氨酸摄取，2）定义代谢机制 LUAD和其他KEAP 1突变型癌症中潜在的丝氨酸依赖性，3）确定膳食丝氨酸限制可以选择性地影响KEAP 1突变体肿瘤的生长，4）分析KEAP 1突变体肿瘤的代谢串扰。在具有NRF 2途径过度活化的癌症中的谷氨酰胺和丝氨酸依赖性。我们的研究将为NRF 2通路过度激活患者的亚分层提供了治疗依据对靶向丝氨酸代谢的治疗有反应，这与精确医学的目标有关。