AUTHOR=Liao Xinmei , Qian Xiaoqing , Zhang Zimu , Tao Yanfang , Li Zhiheng , Zhang Qian , Liang Hui , Li Xiaolu , Xie Yi , Zhuo Ran , Chen Yanling , Jiang You , Cao Haibo , Niu Jiaqi , Xue Cuili , Ni Jian , Pan Jian , Cui Daxiang 

TITLE=ARV-825 Demonstrates Antitumor Activity in Gastric Cancer via MYC-Targets and G2M-Checkpoint Signaling Pathways

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.753119

DOI=10.3389/fonc.2021.753119

ISSN=2234-943X

ABSTRACT=<sec><title>Objective</title><p>Suppression of bromodomain and extra terminal (BET) proteins has a bright prospect to treat MYC-driven tumors. Bromodomain containing 4 (BRD4) is one of the BET proteins. ARV-825, consisting of a BRD4 inhibitor conjugated with a cereblon ligand using proteolysis-targeting chimera (PROTAC) technology, was proven to decrease the tumor growth effectively and continuously. Nevertheless, the efficacy and mechanisms of ARV-825 in gastric cancer are still poorly understood.</p></sec><sec><title>Methods</title><p>Cell counting kit 8 assay, lentivirus infection, Western blotting analysis, Annexin V/propidium iodide (PI) staining, RNA sequencing, a xenograft model, and immunohistochemistry were used to assess the efficacy of ARV-825 in cell level and animal model.</p></sec><sec><title>Results</title><p>The messenger RNA (mRNA) expression of <italic>BRD</italic>4 in gastric cancer raised significantly than those in normal tissues, which suggested poor outcome of patients with gastric cancer. ARV-825 displayed higher anticancer efficiency in gastric cancer cells than OTX015 and JQ1. ARV-825 could inhibit cell growth, inducing cell cycle block and apoptosis <italic>in vitro</italic>. ARV-825 induced degradation of BRD4, BRD2, BRD3, c-MYC, and polo-like kinase 1 (PLK1) proteins in four gastric cancer cell lines. In addition, cleavage of caspase 3 and poly-ADP-ribose polymerase (PARP) was elevated. Knockdown or overexpression <italic>CRBN</italic> could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced <italic>MYC</italic> and <italic>PLK1</italic> expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 <italic>in vivo</italic>.</p></sec><sec><title>Conclusions</title><p>High mRNA expression of <italic>BRD4</italic> in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells <italic>via</italic> transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.</p></sec>