Abstract
Dysregulation of the cell cycle machinery, particularly the overactivation of cyclin-dependent kinases 4 and 6 (CDK4/6), is a hallmark of breast cancer pathogenesis. The introduction of CDK4/6 inhibitors has transformed the treatment landscape for hormone receptor-positive breast cancer by effectively targeting abnormal cell cycle progression. However, despite their initial clinical success, drug resistance remains a significant challenge, with no reliable biomarkers available to predict treatment response or guide strategies for managing resistant populations. Consequently, numerous studies have sought to investigate the mechanisms driving resistance to optimize the therapeutic use of CDK4/6 inhibitors and improve patient outcomes. Here we examine the molecular mechanisms regulating the cell cycle, current clinical applications of CDK4/6 inhibitors in breast cancer, and key mechanisms contributing to drug resistance. Furthermore, we discuss emerging predictive biomarkers and highlight potential directions for overcoming resistance and enhancing therapeutic efficacy.