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

• Published in: Frontiers in oncology 2021-10, Vol.11, p.753119-753119
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: ARV-825; BRD4; c-Myc; gastric cancer; Oncology; PLK1
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2021.753119

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. 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. The messenger RNA (mRNA) expression of 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 . 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 could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced and expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 . High mRNA expression of in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.