Palbociclib (PD 0332991): targeting the cell cycle machinery in breast cancer

The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway, governing the cell cycle restriction point, is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy. Palbociclib (PD 0332991) , a potent and selective inhibitor of CDK4 and CDK6, inhibits proliferation of several Rb-positive cancer cell lines and xenograft models.The basic features and abnormalities of the cell cycle in breast cancer are described, along with their involvement in estrogen signaling and endocrine resistance. The pharmacological features of palbociclib, its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated, and its clinical development in breast cancer described. A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years.The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy. Further, potentially useful combinations are those with drugs targeting mitogenic signaling pathways, such as HER2- and PI3K-inhibitors. Combination with chemotherapy seems more problematic, as antagonism has been reported in preclinical models. The identification of predictive factors, already explored in preclinical studies, must be further refined and validated in clinical trials.