Abstract
BACKGROUND AND OBJECTIVE: Cyclin dependent kinases 4 and 6 (CDK4/6) inhibitors are a class of drugs that are used in the first-line therapy of metastatic estrogen receptor (ER) positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer and in the adjuvant therapy of the same cancers. Three drugs of the class, abemaciclib, palbociclib and ribociclib, are currently approved in partially overlapping indications. This review discusses biomarkers for prediction of efficacy of CDK4/6 inhibitors in breast cancer therapy and the potential for overcoming arising resistance. METHODS: A literature search was performed using the PubMed/Medline database and the proceedings of relevant congresses. Search was concluded on March 31, 2025. KEY CONTENT AND FINDINGS: Combinations of CDK4/6 inhibitors with hormonal agents have improved survival outcomes of metastatic ER-positive/HER2-negative breast cancer patients, but resistance develops almost invariably. In addition, a minority of patients display primary resistance to the combinations. Significant efforts have been committed in determining the mechanisms of resistance with a view to both predicting which patients will become refractory to treatment and to developing new treatments and combinations to circumvent resistance. Alterations in the targeted protein node comprising CDK4/6, cyclin D and retinoblastoma, as well as alterations in upstream pathways that regulate the node and downstream effectors of transcription factor E2F, that execute the cell cycle regulation, have been affirmed as culprits in resistance development. A prominent downstream target of E2F that is repeatedly discussed in several studies is cyclin E. CONCLUSIONS: Key resistance mechanisms interfering with CDK4/6 inhibitor efficacy have been identified but are not yet used clinically. Diverse resistance mechanisms observed in individual cases would require individualized approaches to re-sensitize cancer cells and patients to cell cycle inhibition.