Targeting CDK4/6 in breast cancer

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. CDK4/6 inhibitors have revolutionized the treatment of hormone receptor-positive breast cancer by targeting abnormal cell growth. However, most patients eventually encounter drug resistance, and predicting responses remains a challenge. This Review delves into the mechanisms behind CDK4/6 inhibitor resistance and explores potential strategies to overcome it. The authors provide a comprehensive overview of the cell cycle and the role of CDK4/6 inhibitors, highlighting both genetic and nongenetic factors that drive resistance. Key insights reveal that mutations and alterations in signaling pathways significantly contribute to drug resistance, offering avenues for novel therapeutic targets. Moreover, the Review emphasizes the importance of biomarkers to better predict treatment outcomes. Understanding these resistance mechanisms is pivotal for developing advanced strategies to enhance therapy effectiveness and improve patient prognosis. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.