BET inhibitor and CDK4/6 inhibitor synergistically inhibit breast cancer by suppressing BRD4 stability and DNA damage repair

CDK4/6 inhibitors have demonstrated clinical efficacy in hormone receptor-positive breast cancer. However, their broader clinical application is limited by narrow indications and poorly understood resistance mechanisms. To enhance the therapeutic potential of CDK4/6 inhibitors in breast cancer, we explored their combination with BET inhibitors. While this combination therapy has shown promise in early clinical trials, its underlying mechanisms remain unclear.

Here, we provide evidence that the CDK4/6 inhibitor LY2835219, combined with the BRD4 inhibitor OTX-015, synergistically suppresses the growth of both ER-positive and triple-negative breast cancer cells in vitro and in vivo. Mechanistically, LY2835219 promotes BRD4 degradation via the proteasome pathway by inhibiting CDK4 activity. This destabilization of BRD4 protein enhances the anti-tumor efficacy of the CDK4/6 inhibitor by downregulating the transcription of the DNA damage repair gene *RAD51*. This OTX015 suppression leads to increased γ-H2AX accumulation and DNA double-strand breaks, amplifying the therapeutic effects.

Overall, our findings highlight the potential of combining CDK4/6 and BRD4 inhibitors as a rational therapeutic strategy for breast cancer, offering insights into the mechanisms that support their synergistic efficacy.