Resistance mechanisms and therapeutic strategies of CDK4 and CDK6 kinase targeting in cancer

Cyclin-dependent kinases (CDKs) 4 and 6 (CDK4/6) are important regulators of the cell cycle. Selective CDK4/6 small-molecule inhibitors have shown clinical activity in hormonal receptor-positive (HR+) metastatic breast cancer, but their effectiveness remains limited in other cancer types. CDK4/6 degradation and improved selectivity across CDK paralogs are approaches that could expand the effectiveness of CDK4/6 targeting. Recent studies also suggest the use of CDK4/6-targeting agents in cancer immunotherapy. In this Review, we highlight recent advancements in the mechanistic understanding and development of pharmacological approaches targeting CDK4/6. Collectively, these developments pose new challenges and opportunities for rationally designing more effective treatments.