Novel ROR1 inhibitor ARI-1 suppresses the development of non-small cell lung cancer

doi:10.1016/j.canlet.2019.05.016

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	Novel ROR1 inhibitor ARI-1 suppresses the development of non-small cell lung cancer
	Liu, Xuesha 3; Pu, Wenchen 3; He, Huaiyu 3; Fan, Xin 2,3; Zheng, Yuanyuan 3; Zhou, Jian-Kang 3; Ma, Rui 3; He, Juan 3; Zheng, Yuzhu 3; Wu, Ke 3
刊名	CANCER LETTERS
	2019
卷号	458 页码:76-85
关键词	NSCLC ROR1 EGFR-TKIs Inhibitor PI3K/AKT pathway
ISSN号	0304-3835
DOI	10.1016/j.canlet.2019.05.016
产权排序	3
文献子类	Article
英文摘要	Limited drug response and severe drug resistance confer the high mortality of non-small-cell lung cancer (NSCLC), a leading cause of cancer death worldwide. There is an urgent need for novel treatment against NSCLC. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is aberrantly overexpressed and participats in NSCLC development and EGFR-TKIs-induced drug resistance. Increasing evidences indicate that oncogenic ROR1 is a potential target for NSCLC therapy. However, nearly no ROR1 inhibitor was reported until now. Here, combining the computer-aided drug design and cell-based activity screening, we discover (R)-5,7-bis(methoxymethoxy)-2-(4-methoxyphenyl)chroman-4-one (ARI-1) as a novel ROR1 inhibitor. Biological evaluation demonstrates that ARI-1 specifically targets the extracellular frizzled domain of ROR1 and potently suppresses NSCLC cell proliferation and migration by regulating PI3K/AKT/mTOR signaling in a ROR1-dependent manner. Moreover, ARI-1 significantly inhibits tumor growth in vivo without obvious toxicity. Intriguingly, ARI-1 is effective to EGFR-TKIs-resistant NSCLC cells with high ROR1 expression. Therefore, our work suggests that the ROR1 inhibitor ARI-1 is a novel drug candidate for NSCLC treatment, especially for EGFR-TKIs-resisted NSCLC with high ROR1 expression.
学科主题	Oncogenesis & Cancer Research
URL标识	查看原文
WOS关键词	WNT5A INDUCES ROR1 ; TARGETING ROR1 ; RESISTANCE ; RECEPTOR ; EXPRESSION ; APOPTOSIS ; PATHWAY ; PROTEIN ; DOMAIN
WOS研究方向	Oncology
语种	英语
出版者	ELSEVIER IRELAND LTD
WOS记录号	WOS:000473118900009
内容类型	期刊论文
源URL	[http://210.75.237.14/handle/351003/30941]
专题	国家天然药物工程技术研究中心_天然产物研究
作者单位	1.Chinese Acad Sci, Chengdu Inst Biol, Chengdu 610041, Sichuan, Peoples R China 2.Sichuan Univ, Coll Life Sci, Chengdu 610065, Sichuan, Peoples R China; 3.Sichuan Univ, State Key Lab Biotherapy and Canc Ctr, Natl Clin Res Ctr Geriatr, West China Hosp, Renmin South Rd,Sect 3-17, Chengdu 610041, Sichuan, Peoples R China;
推荐引用方式 GB/T 7714	Liu, Xuesha,Pu, Wenchen,He, Huaiyu,et al. Novel ROR1 inhibitor ARI-1 suppresses the development of non-small cell lung cancer[J]. CANCER LETTERS,2019,458:76-85.
APA	Liu, Xuesha.,Pu, Wenchen.,He, Huaiyu.,Fan, Xin.,Zheng, Yuanyuan.,...&Peng, Yong.(2019).Novel ROR1 inhibitor ARI-1 suppresses the development of non-small cell lung cancer.CANCER LETTERS,458,76-85.
MLA	Liu, Xuesha,et al."Novel ROR1 inhibitor ARI-1 suppresses the development of non-small cell lung cancer".CANCER LETTERS 458(2019):76-85.