CDK4/6 inhibitors in breast cancer therapy: Current practice and future opportunities

Abstract

Dysregulation of the cyclin dependent kinase pathway in luminal breast cancer creates a new therapeutic opportunity for estrogen receptor positive breast cancer. Initial pan-CDK inhibitors were associated with extensive toxicities but in recent years, the development of potent specific CDK inhibitors with favorable tolerability has driven renewed interests in this class of targeted therapies. Palbociclib, ribociclib and abemaciclib are specific CDK4/6 inhibitors that have been approved by the U.S. Food and Drug Administration for use in combination with endocrine therapy for women with advanced hormone receptor positive breast cancer. These three anticancer therapeutics were approved based on progression free survival benefit seen on phase III trials with the most common grade 3 treatment-related side effects being neutropenia, fatigue, nausea and diarrhea. Except for estrogen receptor positivity, no biomarkers predictive of response to CDK4/6 inhibitors have been identified to date. Based on mechanistic insights here described, CDK4/6 inhibitors are currently being explored in combination with other agents, including targeted therapies, immunotherapy and chemotherapy.

Keywords: Breast cancer; CDK4; CDK6; Endocrine resistance; Estrogen receptor.

Fig. 1.

Schematic diagram illustrating the role of CDK4/6 inhibitors in cancer cells. External mitogenic signaling (red arrow) promotes complex formation between CDK4/6 and cyclin D. This CDK4/6-cyclin D complex facilitates the hyper-phosphorylation of RB1, release of E2F transcription factor and transition from G1 into S phase resulting in cell growth. CDK4/6 inhibitors such as palbociclib, ribociclib or abemacicbil (blue arrows) inhibit phosphorylation of RB1 that remains bound to E2F transcription factor and thereby induce cell G1/S cycle arrest arrest resulting in inhibition of cell growth. (Created with BioRender).