Recent advances of highly selective CDK4/6 inhibitors in breast cancer

Abstract

Uncontrolled cell division is the hallmark of cancers. Full understanding of cell cycle regulation would contribute to promising cancer therapies. In particular, cyclin-dependent kinases 4/6 (CDK4/6), which are pivotal drivers of cell proliferation by combination with cyclin D, draw more and more attention. Subsequently, extensive studies were carried out to explore drugs inhibiting CDK4/6 and assess the efficacy and safety of these drugs in cancer, especially breast cancer. Due to the insuperable adverse events and the less activity observed in vivo, the drug development of the initial pan-CDK inhibitor flavopiridol was consequently discontinued, and then highly specific inhibitors were extensively researched and developed, including palbociclib (PD0332991), ribociclib (LEE011), and abemaciclib (LY2835219). Food and Drug Administration has approved palbociclib and ribociclib for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer, and recent clinical trial data suggest that palbociclib significantly improved clinical outcome when combined with letrozole or fulvestrant. Besides, the favorable effects of abemaciclib on prolonging survival of breast cancer patients have also been observed in clinical trials both for single-agent and combination strategy. In this review, we outline the preclinical and clinical advancement of these three orally bioavailable and highly selective CDK4/6 inhibitors in breast cancer.

Keywords: Abemaciclib; Breast cancer; CDK4/6 inhibitors; Palbociclib; Ribociclib; Safety; Treatment resistance.

Fig. 1

Regulation and function of CDK4/6 in cell cycle progression. Active complex of CDK4/6 and cyclin D phosphorylates and inactivates RB protein and then releases transcription factor E2F, triggering the up-regulation of E2F-responsive gene which promotes cell proliferation with cell cycle G1/S transition. The combination of CDK4/6 and cyclin D can also phosphorylates transcription factor FOXM1, resulting in the FOXM1-dependent expression of gene which protects cancer cells from cell cycle block. The kinase activity of CDK4/6 is suppressed by p16^INK4A and pharmacologic CDK4/6 inhibitors including palbociclib, ribociclib and abemaciclib. Cyclin D is regulated by multiple pathways such as ER/PR/AR, NF-kB, MAPKs, STATs, Wnt/β-catenin, and PI3K/AKT/mTOR. Besides, CDK2/cyclin E also participates in the RB phosphorylation. CDK2/cyclin A complex increases in stages S, G2, and M, while CDK1/Cyclin A/B complex mediates the transition from G2 to M stage

Fig. 2

Chemical structures of CDK4/6 inhibitors. The chemical structures of the pan-CDK inhibitor (a) flavopiridol and the highly selective inhibitors including (b) palbociclib (PD0332991), (c) ribociclib (LEE011) and (d) abemaciclib (LY2835219) are shown. The reported half-maximal inhibitory concentration (IC₅₀) values of these inhibitors are shown