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Oncogenic KRAS Induces Arginine Auxotrophy and Confers a Therapeutic Vulnerability to SLC7A1 Inhibition in Non-Small Cell Lung Cancer

文献类型：期刊论文

作者Gai, Xiameng5,6; Liu, Yingluo5; Lan, Xiaojing4,5; Chen, Luoyi5; Yuan, Tao3; Xu, Jun5; Li, Yize5; Zheng, Ying5; Yan, Yiyang5; Yang, Liya5
刊名CANCER RESEARCH
出版日期2024-06-14
卷号84期号:12页码:1963-1977
ISSN号0008-5472
DOI10.1158/0008-5472.CAN-23-2095
通讯作者Liu, Yingluo(yil243@health.ucsd.edu) ; Huang, Min(mhuang@simm.ac.cn) ; Pu, Congying(pucongying@simm.ac.cn)
英文摘要The urea cycle is frequently rewired in cancer cells to meet the metabolic demands of cancer. Elucidation of the underlying mechanism by which oncogenic signaling mediates urea cycle reprogramming could help identify targetable metabolic vulnerabilities. In this study, we discovered that oncogenic activation of KRAS in non-small cell lung cancer (NSCLC) silenced the expression of argininosuccinate synthase 1 (ASS1), a urea cycle enzyme that catalyzes the production of arginine from aspartate and citrulline, and thereby diverted the utilization of aspartate to pyrimidine synthesis to meet the high demand for DNA replication. Specifically, KRAS signaling facilitated a hypoacetylated state in the promoter region of the ASS1 gene in a histone deacetylase 3-dependent manner, which in turn impeded the recruitment of c-MYC for ASS1 transcription. ASS1 suppression in KRAS-mutant NSCLC cells impaired the biosynthesis of arginine and rendered a dependency on the arginine transmembrane transporter SLC7A1 to import extracellular arginine. Depletion of SLC7A1 in both patient-derived organoid and xenograft models inhibited KRAS-driven NSCLC growth. Together, these findings uncover the role of oncogenic KRAS in rewiring urea cycle metabolism and identify SLC7A1-mediated arginine uptake as a therapeutic vulnerability for treating KRAS-mutant NSCLC. Significance: ASS1 deficiency is induced by mutant KRAS in NSCLC to facilitate DNA synthesis and creates a dependency on SLC7A1, revealing dietary arginine restriction and SLC7A1 inhibition as potential therapeutic strategies.
WOS关键词AMINO-ACIDS ; UREA CYCLE ; RAS ; METABOLISM ; DEPENDENCE ; LANDSCAPE ; RESISTANCE ; ENZYMES ; PROTEIN ; ROLES
资助项目National Natural Science Foundation of China (NSFC)[82225046] ; National Natural Science Foundation of China (NSFC)[91957126] ; National Natural Science Foundation of China (NSFC)[22337004] ; National Natural Science Foundation of China (NSFC)[81821005] ; National Natural Science Foundation of China[YDZX20233100004032] ; National Natural Science Foundation of China[20XD1424800] ; Science and Technology Commission of Shanghai Municipality
WOS研究方向Oncology
语种英语
WOS记录号WOS:001247497400003
出版者AMER ASSOC CANCER RESEARCH
源URL[http://119.78.100.183/handle/2S10ELR8/311920]  
专题新药研究国家重点实验室
通讯作者Liu, Yingluo; Huang, Min; Pu, Congying
作者单位1.555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
2.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai, Peoples R China
3.Zhejiang Univ, Inst Pharmacol & Toxicol, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou, Peoples R China
4.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai, Peoples R China
5.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
6.Nanchang Univ, Jiangxi Med Coll, Sch Pharm, Nanchang, Peoples R China
推荐引用方式
GB/T 7714		 Gai, Xiameng,Liu, Yingluo,Lan, Xiaojing,et al. Oncogenic KRAS Induces Arginine Auxotrophy and Confers a Therapeutic Vulnerability to SLC7A1 Inhibition in Non-Small Cell Lung Cancer[J]. CANCER RESEARCH,2024,84(12):1963-1977.
APA Gai, Xiameng.,Liu, Yingluo.,Lan, Xiaojing.,Chen, Luoyi.,Yuan, Tao.,...&Pu, Congying.(2024).Oncogenic KRAS Induces Arginine Auxotrophy and Confers a Therapeutic Vulnerability to SLC7A1 Inhibition in Non-Small Cell Lung Cancer.CANCER RESEARCH,84(12),1963-1977.
MLA Gai, Xiameng,et al."Oncogenic KRAS Induces Arginine Auxotrophy and Confers a Therapeutic Vulnerability to SLC7A1 Inhibition in Non-Small Cell Lung Cancer".CANCER RESEARCH 84.12(2024):1963-1977.

入库方式： OAI收割

来源：上海药物研究所

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