BET inhibitor and CDK4/6 inhibitor synergistically inhibit breast cancer by suppressing BRD4 stability and DNA damage repair
Shuaishuai Chi, Wei Fan, Yangsha Li, Lei Yu, Congzhi Ma, Yanfen Fang, Biyu Yang, Yi Chen, Jian Ning Ding
Abstract
• Abemaciclib and OTX-015 exhibit a synergistic anti-tumor effect in ER + and triple-negative breast cancer in vitro and in vivo . • The synergistic effect of combining CDK4/6 inhibitors and BET inhibitors is mediated by promoting DNA damage and cell apoptosis. • CDK4 inhibition can promote the degradation of BRD4 through the proteasome pathway, leading to the downregulation of RAD51 expression and inhibition of DNA damage repair. CDK4/6 inhibitors have shown clinical benefits in hormone receptor positive breast cancer. However, monotonous indications and unclear resistance mechanisms greatly limit the clinical application of these inhibitors. We attempt to improve the therapeutic effect of CDK4/6 inhibitors against breast cancer by combination with BET inhibitors. Although this combination therapy has begun to be studied in recent clinical trials, the mechanism of action is not clear. We provide the evidence that CDK4/6 inhibitor LY2835219 plus BRD4 inhibitor OTX-015 synergistically inhibits both ER positive and triple-negative breast cancer cells growth in vitro and in vivo . Mechanistically, LY2835219 accelerates the degradation of BRD4 through the proteasome pathway via inhibition of CDK4 activity. This instability of BRD4 protein in turn enhances the anti-tumor effect of CDK4/6 inhibitor by suppressing transcription of DNA damage repair gene RAD51 , and synergistically promotes γ-H2AX accumulation and DNA double-strand breaks. Overall, we demonstrated the potential combined therapeutic value of CDK4/6 and BRD4 inhibitors and elucidated the mechanisms, which may provide a new rational approach for breast cancer patients.