机构：[1]Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.[2]Department of Thoracic Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.四川大学华西医院[3]State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.[4]Medical Research Institute, Wuhan University, Wuhan, China.[5]Tongji University Cancer Center, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China.
The bromodomain and extra-terminal domain (BET) proteins are promising therapeutic targets to treat refractory solid tumors; however, inherent resistance remains a major challenge in the clinic. Recently, the emerging role of the oncoprotein B cell lymphoma 6 (BCL6) in tumorigenesis and stress response has been unveiled. Here, we demonstrate that BCL6 was upregulated upon BET inhibition in KRAS-mutant cancers, including non-small-cell lung cancer (NSCLC). We further found that BRD3, not BRD2 or BRD4, directly interacted with BCL6 and maintained the negative autoregulatory circuit of BCL6. Disrupting this negative autoregulation by BET inhibitors (BETi) resulted in a striking increase in BCL6 transcription, which further activated the mTOR signaling pathway through repression of the tumor suppressor death-associated protein kinase 2. Importantly, pharmacological inhibition of either BCL6 or mTOR improved the tumor response and enhanced the sensitivity of KRAS-mutant NSCLC to BETi in both in vitro and in vivo settings. Overall, our findings identify a mechanism of BRD3-mediated BCL6 autoregulation and further develop an effective combinatorial strategy to circumvent BETi resistance in KRAS-driven NSCLC.
基金：
This work was sponsored by the National Natural Science Foundation
of China (81874207, 82073073, and 81672758, to XP;
81830083, to ML; and 81773075, to ZC); the Shanghai Pujiang
Program (18PJD014, to XP); the and Shanghai International
Cooperation and Exchange Project (18410720600, to ZC).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2021]版：
大类|1 区医学
小类|1 区医学：研究与实验
最新[2023]版：
大类|1 区医学
小类|1 区医学：研究与实验
第一作者：
第一作者机构：[1]Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.[2]Department of Thoracic Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China.
共同第一作者：
通讯作者：
通讯机构：[1]Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.[*1]Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Rd., Shanghai 200241, China
推荐引用方式(GB/T 7714)：
Guo Jiawei,Liu Yanan,Lv Jing,et al.BCL6 confers KRAS-mutant non-small-cell lung cancer resistance to BET inhibitors.[J].The Journal of clinical investigation.2021,131(1):doi:10.1172/JCI133090.
APA：
Guo Jiawei,Liu Yanan,Lv Jing,Zou Bin,Chen Zhi...&Pang Xiufeng.(2021).BCL6 confers KRAS-mutant non-small-cell lung cancer resistance to BET inhibitors..The Journal of clinical investigation,131,(1)
MLA：
Guo Jiawei,et al."BCL6 confers KRAS-mutant non-small-cell lung cancer resistance to BET inhibitors.".The Journal of clinical investigation 131..1(2021)
医学