期刊
CANCER LETTERS
卷 458, 期 -, 页码 76-85出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2019.05.016
关键词
NSCLC; ROR1; EGFR-TKIs; Inhibitor; PI3K/AKT pathway
类别
资金
- National Key R&D Program of China [2016YFA0502204, 2017YFA0504304]
- National Natural Science Foundation of China [81772960, 81572739, 81702980]
- China Postdoctoral Science Foundation [2018M640925]
- Post-Doctor Research Project, West China Hospitial, Sichuan University [2018HXBH014]
- Sichuan Science and Technology Program [2019JDTD0013]
- 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University [ZYJC18030]
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.
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