Mechanism of CDK4/6 Inhibitor Resistance in Hormone Receptor-positive Breast Cancer and Alternative Treatment Strategies

Breast cancer (BC) is a common malignancy in women, with hormone receptor (HR)-positive subtype responsible for approximately 70% of cases. Currently, patients with metastatic HR-positive BC rely on endocrine therapy and cyclin-dependent kinase (CDK)-4/6 inhibitors for treatment. Currently, approved CDK4/6 inhibitors include palbociclib, ribociclib, and abemaciclib. However, clinical evidence of CDK-4/6 inhibitor resistance is emerging, suggesting that the gap in the knowledge of its resistance mechanism requires further investigation. This review discusses the mechanisms of CDK4/6 inhibitor resistance in BC, including both intrinsic and extrinsic mechanisms. We also discuss possible alternative strategies to overcome CDK4/6 inhibitor resistance in future clinical applications.