Novel ROR1 inhibitor ARI-1 suppresses the development of non-small cell lung cancer.
Cancer Lett
; 458: 76-85, 2019 08 28.
Article
em En
| MEDLINE
| ID: mdl-31125641
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cromonas
/
Carcinoma Pulmonar de Células não Pequenas
/
Receptores Órfãos Semelhantes a Receptor Tirosina Quinase
/
Neoplasias Pulmonares
Tipo de estudo:
Clinical_trials
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cancer Lett
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China