CDK4/6 Inhibitors in Breast Cancer Therapy: Mechanisms, Resistance, and Emerging Opportunities.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have significantly changed the treatment approach for hormone-receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HER2-) breast cancer in both metastatic and high-risk early-stage settings. In combination with endocrine therapy, these agents consistently improve progression-free survival, and several phase III trials have demonstrated overall survival benefit in defined populations. Their clinical activity is supported by a well-established biologic rationale targeting dysregulated cell cycle progression, a key feature of HR+ breast cancer, which drives tumor proliferation. Despite these advances, resistance remains a clinical limitation in advanced disease. Multiple mechanisms have been identified, including loss of RB1 function; amplification of CDK6, activation of cyclin E CDK2 signaling; upregulation of bypass pathways such as PI3K, AKT, mTOR, and FGFR; and acquired alterations in estrogen receptor signaling, including ESR1 mutations. Circulating tumor DNA assays are increasingly used in clinical practice and clinical trials to detect emerging genomic alterations that may allow earlier modification of therapy based on molecular progression. The post-CDK4/6-inhibitor treatment landscape has expanded substantially and now includes treatment options such as switching CDK4/6 inhibitors, targeting the PI3K-AKT pathway in patients selected for mutation, use of oral selective estrogen receptor degraders, and incorporation of antibody-drug conjugates. Ongoing studies evaluating CDK2 inhibitors, CDK4-selective agents, immunotherapy combinations, and circulating tumor DNA (ctDNA)-guided strategies aim to further refine treatment sequencing and improve long-term outcomes in HR+/HER2- breast cancer.