The Role of CD4/6 Inhibitors in Breast Cancer Treatment

Abstract

Over the last decade, treatment paradigms for breast cancer have undergone a renaissance, particularly in hormone-receptor-positive/HER2-negative breast cancer. These revolutionary therapies are based on the selective targeting of aberrancies within the cell cycle. This shift towards targeted therapies has also changed the landscape of disease monitoring. In this article, we will review the fundamentals of cell cycle progression in the context of the new cyclin-dependent kinase inhibitors. In addition to discussing the currently approved cyclin-dependent kinase inhibitors for breast cancer, we will explore the ongoing development and search for predictive biomarkers and modalities to monitor treatment.

Keywords: CDK inhibitors; ER+/HER2− breast cancer; ctDNA.

Figure 1

Cyclin-CDK-E2F-Rb pathway with estrogen signaling resulting in amplification of cyclin D is shown. In box 1, estrogen (E2) binds with estrogen receptor (ER) and is translocated to the nucleus, where it, then promotes the transcription of the CCND1 gene resulting in cyclin D1. Pro-mitogenic signals and other pathways can also amplify cyclin D1 transcription, which is discussed elsewhere. In box 2, cyclin D1 then binds with cyclin-dependent kinase (CDK) 4 and 6 to create an activated holoenzyme. In box 3, this cyclin-CDK 4/6 complex phosphorylates retinoblastoma protein (Rb), which results in the dissociation of Rb from the E2F transcription factor seen in box 4. In box 5, the now free E2F transcription factor promotes the downstream cascade of protein synthesis, ultimately transitioning the cell from G1 to S phase. Further, E2F transcribes the CDK2NA gene, which results in the synthesis of p16INK4a, a potent inhibitor of the cyclin-CDK 4/6 complex. This results in a negative feedback loop, which arrests the progression of the cell cycle.