癌症研究
ROR1型
PI3K/AKT/mTOR通路
医学
癌症
肺癌
埃罗替尼
药理学
吉非替尼
蛋白激酶B
细胞生长
酪氨酸激酶
酪氨酸激酶抑制剂
信号转导
表皮生长因子受体
生物
内科学
受体
生长因子
细胞生物学
血小板源性生长因子受体
遗传学
作者
Xuesha Liu,Wenchen Pu,Huaiyu He,Xin Fan,Yuanyuan Zheng,Jiankang Zhou,Rui Ma,Jinzhi He,Yuzhu Zheng,Ke Wu,Yun Zhao,Shengyong Yang,Chun Wang,Yuquan Wei,Xiawei Wei,Yong Peng
标识
DOI:10.1016/j.canlet.2019.05.016
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.
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