2. Academic Validation
  3. Novel ROR1 inhibitor ARI-1 suppresses the development of non-small cell lung cancer

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

  • Cancer Lett. 2019 Aug 28:458:76-85. doi: 10.1016/j.canlet.2019.05.016.
Xuesha Liu 1,  Wenchen Pu 1,  Huaiyu He 1,  Xin Fan 2,  Yuanyuan Zheng 1,  Jian-Kang Zhou 1,  Rui Ma 1,  Juan He 1,  Yuzhu Zheng 1,  Ke Wu 1,  Yun Zhao 3,  Sheng-Yong Yang 1,  Chun Wang 4,  Yu-Quan Wei 1,  Xia-Wei Wei 5,  Yong Peng 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; College of Life Science, Sichuan University, Chengdu 610065, China.
  • 3 College of Life Science, Sichuan University, Chengdu 610065, China.
  • 4 Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
  • 5 State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: xiaweiwei@scu.edu.cn.
  • 6 State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: yongpeng@scu.edu.cn.
PMID: 31125641 DOI: 10.1016/j.canlet.2019.05.016
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.

Keywords

EGFR-TKIs; Inhibitor; NSCLC; PI3K/AKT pathway; ROR1.

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