Updated Review Article: Cyclin-Dependent Kinase 4/6 Inhibitor Impact, FDA Approval, and Resistance Pathways

To describe the mechanism of cyclin-dependent kinase (CDK) 4/6 inhibitors, mechanisms of resistance, and summarize various clinical trials used to determine the efficacy and safety of CDK4/6 inhibitor used for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-), advanced or metastatic breast cancer. An extensive literature search using PubMed and notable sources was performed (2016 to February 2022) using the following search terms: CDK4/6 inhibitors, palbociclib, abemaciclib, ribociclib, CDK4/6 inhibitor resistance, FAT1 gene, luminal A breast cancer, luminal B breast cancer, HR+/HER2- breast cancer. Abstracts from conferences, national clinical trials, and drug monographs were reviewed. Relevant clinical studies or those conducted in humans and updated clinical trials were considered. The various clinical trials reviewed and results have led to numerous studies and expansions of U.S. Food and Drug Administration (FDA) approval. Although the use of CDK4/6 inhibitors has improved progression-free survival in patients with HR+, HER2- breast cancer, studies have shown that resistance pathways can cause cells to be insensitive to CDK4/6 inhibitors, leading to continued cell proliferation. CDK4/6 inhibitors are recommended as first-line therapy in combination with endocrine therapy for patients with HR+/HER2- advanced breast cancer. However, mutations and acquired resistance can occur that affect a patient's response to treatment. Additional research needs to be conducted on strategies to overcome resistance and determine how ethnicity plays a role in resistance pathways.