Cyclin-dependent kinase 4/6 inhibitors in breast cancer: palbociclib, ribociclib, and abemaciclib.

Abstract

The cyclin D-cyclin dependent kinase (CDK) 4/6-inhibitor of CDK4 (INK4)-retinoblastoma (Rb) pathway plays a crucial role in cell cycle progression and its dysregulation is an important contributor to endocrine therapy resistance. CDK4/6 inhibitors trigger cell cycle arrest in Rb protein (pRb)-competent cells. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising results of efficacy and manageable safety profiles. The main objective of this review is to discuss preclinical and clinical data to date, and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in breast cancer. A literature search of above topics was carried out using PubMed and data reported at international oncology meetings and clinicaltrials.gov were included. The highly selective oral CDK4/6 inhibitors have been tested in combination with endocrine therapy in Phase III studies in metastatic breast cancer. Results led to the US Food and Drug Administration approval of palbociclib (PD0332991) and ribociclib (LEE011), and abemaciclib (LY2835219) is in development. Studies of these agents, in combination with endocrine therapy, are also underway in ER-positive early breast cancer in the neoadjuvant and adjuvant settings. Moreover, they are also being investigated with other agents in the advanced setting and in triple negative breast cancer. After having demonstrated impressive activity in ER-positive, HER2-negative metastatic breast cancer, currently CDK4/6 inhibitors are in further development. It is obvious that this class of agents with their efficacy, low and easily manageable toxicity, and oral dosage is a very important treatment option for breast cancer patients.