Crystal structure of active CDK4-cyclin D and mechanistic basis for abemaciclib efficacym

Despite the therapeutic relevance of CDK4/6, the crystal structure of active CDK4 has yet to be elucidated, and the mechanistic rationale for sustained cell cycle inhibition is not fully understood. Here, we describe the co-crystal structure of active CDK4-cyclin D3 bound to the CDK4/6 inhibitor abemaciclib and discuss the key aspects of the catalytically-competent complex. Mechanistically, we show that CDK4/6i, palbociclib and abemaciclib, stabilize active CDK4-cyclin D complex and selectively displace p21 from CDK4-cyclin D complex in responsive tumor cells. Further, we demonstrate that sustained binding of abemaciclib to CDK4 prevents rebound activation of downstream signalling, leading to potent cell cycle inhibition in breast cancer cell lines. Overall, our study provides novel insights demonstrating that prolonged treatment and composition of the CDK4/6-cyclin D complex are both critical determinants of abemaciclib sensitivity and important factors to identify potential combination therapies that may overcome mechanisms of resistance.