Reciprocal positive regulation between BRD4 and YAP in GNAQ-mutant uveal melanoma cells confers sensitivity to BET inhibitors

作者：Zhang, Gui-Ming; Huang, Si-Si; Ye, Lin-Xuan; Liu, Xiao-Lian; Shi, Wen-Hui; Ren, Zhong-Lu; Zhou, Run-Hua; Zhang, Jia-Jie; Pan, Jing-Xuan; Liu, Shu-Wen; Yu, Le^*; Li, Yi-Lei^*

来源：Pharmacological Research, 2022, 184: 106464.

DOI：10.1016/j.phrs.2022.106464

• Uveal melanoma
• Targeted therapy
• GNAQ mutations
• YAP
• BRD4
• BET inhibitors

Uveal melanoma (UM) is the most common intraocular cancer in adults. UMs are usually initiated by a mutation in GNAQ or GNA11 (encoding Gq or G11, respectively), unlike cutaneous melanomas (CMs), which usually carry a BRAF or NRAS mutation. Currently, there are no clinically effective targeted therapies for UM carrying Gq/11 mutations. Here, we identified a causal link between Gq activating mutations and hypersensitivity to bromo-domain and extra-terminal (BET) inhibitors. BET inhibitors transcriptionally repress YAP via BRD4 regardless of Gq mutation status, independently of Hippo core components LATS1/2. In contrast, YAP/TAZ downregulation reduces BRD4 transcription exclusively in Gq-mutant cells and LATS1/2 double knockout cells, both of which are featured by constitutively active YAP/TAZ. The transcriptional interdependency between BRD4 and YAP iden-tified in Gq-mutated cells is responsible for the preferential inhibitory effect of BET inhibitors on the growth and dissemination of Gq-mutated UM cells compared to BRAF-mutated CM cells in both culture cells and animal models. Our findings suggest BRD4 as a viable therapeutic target for Gq-driven UMs that are addicted to un-restrained YAP function.

• 单位
  中山大学; 广东药学院; 南方医科大学