Overcoming Resistance to CDK4/6 inhibitors in Hormone Receptor positive, HER2 negative breast cancer: Innovative Combinations and Emerging Strategies
Federica Giugliano, Carmine De Angelis, Barbara Pistilli, Giulia Viale, Giampaolo Bianchini, Mario Giuliano, Luca Malorni, Beatrice Taurelli Salimbeni, Angela Espósito, Antonio Giordano, Timothy A. Yap, Giuseppe Curigliano, Carmen Criscitiello
Abstract
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.