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

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

doi:10.3389/fonc.2021.753119

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

Front Oncol. 2021 Oct 18:11:753119. doi: 10.3389/fonc.2021.753119. eCollection 2021.

Authors

Xinmei Liao¹, Xiaoqing Qian^{1

2}, Zimu Zhang³, Yanfang Tao³, Zhiheng Li³, Qian Zhang¹, Hui Liang⁴, Xiaolu Li³, Yi Xie³, Ran Zhuo³, Yanling Chen³, You Jiang³, Haibo Cao³, Jiaqi Niu¹, Cuili Xue¹, Jian Ni¹, Jian Pan³, Daxiang Cui^{1

4}

Affiliations

¹ Institute of Nano Biomedicine and Engineering, Shanghai Engineering Research Centre for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, China.
² School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
³ Institute of Pediatric Research, Children's Hospital of Soochow University, Suzhou, China.
⁴ Institute of Nanomedicine, National Engineering Research Centre for Nanotechnology, Shanghai, China.

Abstract

Objective: 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.

Methods: 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.

Results: The messenger RNA (mRNA) expression of BRD4 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 in vitro. 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 CRBN could increase or decrease, respectively, the ARV-825 IC50 of gastric cancer cells. ARV-825 reduced MYC and PLK1 expression in gastric cancer cells. ARV-825 treatment significantly reduced tumor growth without toxic side effects and downregulated the expression of BRD4 in vivo.

Conclusions: High mRNA expression of BRD4 in gastric cancer indicated poor prognosis. ARV-825, a BRD4 inhibitor, could effectively suppress the growth and elevate the apoptosis of gastric cancer cells via transcription downregulation of c-MYC and PLK1. These results implied that ARV-825 could be a good therapeutic strategy to treat gastric cancer.

Keywords: ARV-825; BRD4; PLK1; c-Myc; gastric cancer.