CDK4/6 Inhibitors in Breast Cancer: Clinical Applications, Translational Insights, and Future Directions

Abstract

Simple Summary Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have transformed the treatment landscape for hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) breast cancer. This review examines the clinical development of palbociclib, ribociclib, and abemaciclib across both early-stage and metastatic settings, revealing clinically meaningful differences in efficacy that challenge the notion of a uniform class effect. We discuss established and emerging resistance mechanisms, including RB1 loss, ESR1 mutations, and APOBEC3-mediated mutagenesis, and propose a conceptual framework that classifies resistance as either target-driven or bypass-driven to inform rational treatment sequencing. Emerging therapeutic strategies—including next-generation protein degraders (PROTACs), oral selective estrogen receptor degraders, antibody–drug conjugates, and autophagy inhibitors—are highlighted as promising approaches to overcome or circumvent resistance. Looking forward, the greatest advances will likely come not from developing additional agents alone, but from more intelligent use of existing therapies through refined biomarker-guided patient selection, optimized treatment sequencing, and equitable global access.