CDk Inhibitor for Treatment of Breast Cancer

Abstract

AbstractA complicated interaction of Cyclins and cyclin-dependent kinases (CDKs) drives the mammalian cell cycle and one of the main causes or hallmarks of cancer is the deregulation of this system. The abnormality in the cell cycle regulation often leads to the cancerous growth of cells. The mitogenesis induced by steroids and growth factors in breast epithelium involves two important cyclin types including D and E. The main function of these Cyclins is the progress from G1 to S phase during normal cell division. Over-expression of cyclins especially type D1 and E1in mammary epithelial cells causes metastatic breast cancer (MBC) by influencing the process of cell division. The early results of CDK inhibitors with wide action were mostly unsatisfactory. Preclinical and phase I/II studies employing Palbociclib (PD-0332991), a novel, oral, reversible CDK4/6 inhibitor have established CDK4/6 as a promising target in ER+ breast tumors. Palbociclib, Abemaciclib, and LEE011 are three oral CDK4/6 inhibitors that have evolved. These inhibitors have a primarily hematologic toxicity profile in early phase I and II trials, with little neutropenia and variable gastrointestinal effects. Palbociclib in combination with endocrine therapy has shown encouraging results in phase 2 clinical work about breast cancer when compared to endocrine therapy alone. The introduction of CDK 4/6 inhibitors has altered the treatment of HR+ MBC and for individuals who have already been treated, Abemaciclib is approved as a monotherapy. Small medicines that inhibit CDKs have shown considerable promise in the treatment of breast cancer, and some sufferer with metastatic illness has received them as standard of care. As the list of medications for CDK inhibitors grows, it is more important to understand how these medications work and how they interact with other targeted therapies. Second-generation CDK inhibitors show encouraging therapeutic benefits with a manageable safety profile as compared to more toxic and non-selective generation first cyclin-dependent kinase inhibitors (example: Flavopiridol). First CDK4/6 inhibitor to get FDA approval, Palbociclib (in Feb 2015) was used for the treatment of MBC in coupling with letrozole, additionally in coupling with Fulvestrant for MBC that had progressed on previous endocrine therapy. Studies are also being carried using various CDK (4/6) inhibitors, such as Ribociclib and Abemaciclib as a monotherapy and in conjunction with endocrine or anti-human epidermal growth factor receptor (EER) therapy for MBC. Ongoing clinical trials should furnish more evidence to help and show the suitable use of these drugs and identify patient groups that will benefit the most. The present usage, current issues, and research trends of CDK (4/6) inhibitors in HR+ MBC will be the focus of this chapter.KeywordsBreast cancerCell cycleCyclinsMitogensCDKsCyclin inhibitorsTherapy