CDK Inhibitor Landscape: From Approved CDK4/6 Drugs to Next-Generation CDK2 Strategies
CDK4/6 inhibitors have transformed HR+/HER2− breast cancer treatment, while emerging resistance mechanisms are driving development of selective CDK2 inhibitors and dual CDK2/4 strategies to address treatment failure.
The clinical approval of CDK4/6 inhibitors in the late 2010s marked a watershed moment in the treatment of ER+/HER2- breast cancer, as they transformed the standard of care and improved patient outcomes. This milestone was the result of decades of research, tracing back to early pan-CDK inhibitors and culminating in the development of selective CDK4/6 compounds.
CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib have reshaped HR+/HER2− breast cancer treatment, delivering marked gains in progression-free survival when combined with endocrine therapy. While all share core binding features, differences in kinase selectivity translate to varied dosing schedules and safety profiles.
Emerging resistance mechanisms often involving RB1 loss or CDK2 upregulation are driving next‑generation CDK4‑selective and dual CDK2/4 strategies. Highly potent and selective CDK2 inhibitors are being evaluated in the clinic as single agents and in combination regimens, particularly to address resistance to CDK4/6 inhibitors.
New modalities, including targeted protein degraders, are also coming to the fore. The leading compounds in the race to develop the first clinically approved CDK2 inhibitor drug, as well as the new modalities being explored preclinically, represent the next frontier in addressing treatment resistance in breast cancer.