AUTHOR=Li Zhiheng , Lim Su Lin , Tao Yanfang , Li Xiaolu , Xie Yi , Yang Chun , Zhang Zimu , Jiang You , Zhang Xianbing , Cao Xu , Wang Hairong , Qian Guanghui , Wu Yi , Li Mei , Fang Fang , Liu Ying , Fu Mingcui , Ding Xin , Zhu Zhenghong , Lv Haitao , Lu Jun , Xiao Sheng , Hu Shaoyan , Pan Jian 

TITLE=PROTAC Bromodomain Inhibitor ARV-825 Displays Anti-Tumor Activity in Neuroblastoma by Repressing Expression of MYCN or c-Myc

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.574525

DOI=10.3389/fonc.2020.574525

ISSN=2234-943X

ABSTRACT=<p>Neuroblastoma (NB) is one of the most common solid tumors in childhood. To date, targeting <italic>MYCN</italic>, a well-established driver gene in high-risk neuroblastoma, is still challenging. In recent years, inhibition of bromodomain and extra terminal (BET) proteins shows great potential in multiple of <italic>Myc</italic>-driven tumors. ARV-825 is a novel BET inhibitor using proteolysis-targeting chimera (PROTAC) technology which degrades target proteins by the proteasome. In this study, we investigated the effect of ARV-825 in neuroblastoma <italic>in vitro</italic> and <italic>in vivo</italic>. Our results showed that ARV-825 treatment robustly induced proliferative suppression, cell cycle arrest, and apoptosis in NB cells. Moreover, ARV-825 efficiently depleted BET protein expression, subsequently repressing the expression of <italic>MYCN</italic> or <italic>c-Myc</italic>. In the NB xenograft model, ARV-825 profoundly reduced tumor growth and led to the downregulation of BRD4 and <italic>MYCN</italic> expression in mice. Taken together, these findings provide evidence that PROTAC BET inhibitor is an efficient way to achieve <italic>MYCN</italic>/<italic>c-Myc</italic> manipulation, and ARV-825 can be used as a potential therapeutic strategy for the treatment of neuroblastoma.</p>