ARV-825 Showed Antitumor Activity against BRD4-NUT Fusion Protein by Targeting the BRD4.

Autor: Yang L; Applied Biology Laboratory, College of Pharmaceutical and Biological Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China., Jing Y; Applied Biology Laboratory, College of Pharmaceutical and Biological Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China., Xia X; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China., Yin X; Applied Biology Laboratory, College of Pharmaceutical and Biological Engineering, Shenyang University of Chemical Technology, Shenyang 110142, China.; Roc Rock Biotechnology (Shenzhen), Shenzhen 518118, China.
Jazyk: angličtina
Zdroj: Journal of oncology [J Oncol] 2023 Dec 14; Vol. 2023, pp. 9904143. Date of Electronic Publication: 2023 Dec 14 (Print Publication: 2023).
DOI: 10.1155/2023/9904143
Abstrakt: Objective: The bromodomain-containing 4 (BRD4) is a member of the bromodomain and extra terminal domain (BET) family, which is an important epigenetic reader. It is currently a promising oncology target. In some tumors, BET bromodomain inhibitors have demonstrated promising results. Proteolysis-targeting methods (PROTAC), which rapidly and effectively degrade BRD4, have displayed considerable potential in the treatment of tumors in recent years. The purpose of this study is to examine the potential impact of BRD4 PROTAC compounds ARV-825 on oncogene BRD4-NUT fused protein in NUT carcinoma.
Methods: The effectiveness of ARV-825 was evaluated at the cellular level using the cell counting kit 8 test, wound healing, cell transfection, western blotting analysis, and RNA sequencing. The effectiveness of ARV-825 was also examined in vivo using a xenograft model.
Results: The BRD4-NUT fusion gene was overexpressed in 3T3 cells, and the pathogenic fusion gene was simulated. The results showed that the overexpression of BRD4-NUT could promote the proliferation and migration of 3T3 cells, but the expression of BRD4 protein was degraded after the addition of the novel cereblon-based PROTAC compound ARV-825 against BRD4, resulting in inhibition of BRD4-NUT 3T3 cell proliferation and migration. Further RNA-seq analysis showed that overexpression of BRD4-NUT was accompanied by increased expression of gene (e.g., Myc, E2F, TRAFs, Wnt, Gadd45g, and Sox6) with significantly enriched pathway (e.g., small cell lung cancer, NF-kappa B signaling pathway, and breast cancer), promoted cell cycle from G 1 phase to S phase, and increased cell proliferation and migration, activated the antiapoptosisi signal, led to abnormal cell growth, and ultimately led to tumorigenesis. The addition of ARV-825 effectively rescued this process and effectively inhibited cell vitality, proliferation, and migration. In vivo studies demonstrated that treatment with ARV-825 greatly suppressed tumor growth without causing harmful side effects and downregulated the BRD4-NUT expression level.
Conclusion: Through the induction of BRD4 protein degradation, ARV-825 can successfully limit BRD4-NUT 3T3 cell proliferation in vitro and in vivo. These findings suggested that the BRD4 inhibitor ARV-825 would be an effective therapeutic strategy for treating NUT carcinoma that with the genetic feature of BRD4-NUT fusion event.
Competing Interests: The authors declare that they have no conflicts of interest.
(Copyright © 2023 Liu Yang et al.)
Databáze: MEDLINE
Externí odkaz: