Targeting Cell Cycle in Breast Cancer: CDK4/6 Inhibitors

Abstract

Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment.

Keywords: CDK4/6 inhibitors; cancer; cell cycle; cyclin-dependent kinase; hormone receptors; hormone therapy; metastatic breast cancer; therapies.

Figure 1

Mechanism of action of CDK4/6 inhibitors. Activation of upstream signaling pathways, such as MAPK, PI3K, and ER, regulate the progression of cell cycle by promoting the formation of complex cyclin D-CDK4/6, which selectively phosphorylates and inactivates pRb protein. Rb proteins limit the expression of many E2F target genes which are involved in cell cycle progression, DNA replication, and mitotic progression. CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) selectively inhibit the downstream CDK4/6-mediated phosphorylation of Rb, leading to cell cycle arrest in G0/G1 phase. Combination strategies are focused on dual blockade of CDK4/6 and upstream signaling, mainly mediated by ER, MAPK pathway and PI3K/AKT/mTOR pathway.