期刊
PHARMACOLOGICAL RESEARCH
卷 184, 期 -, 页码 -出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.phrs.2022.106464
关键词
Uveal melanoma; Targeted therapy; GNAQ mutations; YAP; BRD4; BET inhibitors
资金
- National Natural Science Foundation of China
- Guangdong Basic and Applied Basic Research Foundation
- Open Research Funds of the State Key Laboratory of Ophthalmology
- China International Medical Foundation
- Guangdong Province Yiyang Health Charity Foundation
- [81973357]
- [2020A1515010027]
- [2022A1515011824]
- [2022KF06]
This study identifies a causal link between Gq activating mutations and hypersensitivity to BET inhibitors, suggesting BRD4 as a potential therapeutic target for Gq-driven Uveal melanoma.
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.
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