Novel ROR1 inhibitor ARI-1 suppresses the development of non-small cell lung cancer. (28th August 2019)

• Record Type: Journal Article
• Authors: Liu, Xuesha; Pu, Wenchen; He, Huaiyu; Fan, Xin; Zheng, Yuanyuan; Zhou, Jian-Kang; Ma, Rui; He, Juan; Zheng, Yuzhu; Wu, Ke; Zhao, Yun; Yang, Sheng-Yong; Wang, Chun; Wei, Yu-Quan; Wei, Xia-Wei; Peng, Yong
• Is Part Of: Cancer letters. Volume 458(2019)
• Page Start: 76
• Page End: 85
• Publication Date: 2019-08-28
• Subjects: NSCLC -- ROR1 -- EGFR-TKIs -- Inhibitor -- PI3K/AKT pathway; NSCLC non-small cell lung cancer -- EGFR epidermal growth factor receptor -- ROR1 receptor tyrosine kinase-like orphan receptor 1 -- SPR surface plasmon resonance -- EGFR-TKIs epidermal growth factor receptor-tyrosine kinase inhibitors -- PI3K phosphatidylinositol 3 kinase -- AKT protein kinase B -- mTOR mammalian target of rapamycin -- HER3(ERBB3) human epidermal growth factor receptor 3 -- IGF-IR insulin-like growth factor 1 receptor -- CAR-T chimeric antigen receptor T cells -- CADD computer-aided drug design -- CETSA cellular thermal shift assay -- EdU 5-ethynyl-2′-deoxyuridine -- ADMET absorption, distribution, metabolism, excretion and toxicity -- TOPKAT toxicity prediction by komputer assisted technology -- IHC immunohistochemical -- RIP3 receptor-interacting serine/threonine-protein kinase 3; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2019.05.016
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: Discovery of the novel ROR1 inhibitor ARI-1 specifically targeting the extracellular frizzled domain of ROR1. The ROR1 inhibitor ARI-1 potently suppresses the development of NSCLC through blocking PI3K/AKT/mTOR signaling. ARI-1 significantly inhibits tumor growth in vivo without obvious toxicity.