Triple negative breast cancer represents the most clinically challenging subtypes of breast cancer for which targeted therapeutics are still lacking. BET proteins have emerged as new therapeutic targets for human cancer and other diseases.We have developed a highly potent BET degrader, BETd-246, with an exceptional selectivity based upon a new class of BET inhibitor, BETi-211, and investigated its therapeutic potential and mechanisms of action in TNBC. BETd-246 induces degradation of BET proteins at low nanomolar concentrations within 1 hour, leading to potent anti-proliferative activity and strong apoptosis induction in the majority of TNBC cell lines, and is much more effective than the BETi-211 treatment. RNA-seq analysis reveals that degradation of BET proteins by BETd-246 elicits distinct transcriptional response than BET BD inhibition in TNBC cell lines. Transcriptomic analysis also shows a number of proliferation and survival-related genes were differentially regulated by BETd-246 and BETi-211 which were confirmed by quantitative RT-PCR. Mechanistically, down-regulation of MCL1 by BETd-246 plays a key role in the robust apoptosis induction in TNBC cell lines. In in vivo models, BETd-246 effectively degrades BET proteins and suppresses MCL1 expression in xenograft tumor tissues and exhibits a strong antitumor activity at well-tolerated dose-schedules in mice. Our data strongly suggest that targeting BET protein degradation is an exciting therapeutic strategy for TNBC.

Citation Format: Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Shaomeng Wang. Therapeutic targeting of bromodomain and extra-terminal proteins degradation in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5074. doi:10.1158/1538-7445.AM2017-5074