Overcoming Resistance to CDK4/6 inhibitors in Hormone Receptor positive, HER2 negative breast cancer: Innovative Combinations and Emerging Strategies

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) improve outcomes patients affected by metastatic and early-stage hormone receptor-positive, HER2-negative breast cancer. However, approximately 20% of these tumors exhibit intrinsic resistance to such therapies, and most develop acquired resistance mechanisms that drive progression. Biomarker analyses of biological samples from patients treated with CDK4/6i plus ET have identified potential targets for therapeutic combinations. In this review, we discuss the mechanisms of action and resistance to CDK4/6i, providing a comprehensive overview of emerging efficacy and safety data, biomarker-driven strategies, and ongoing clinical trials. Finally, we delineate key research priorities aimed at guiding the development of innovative therapeutic combinations.