Ribociclib (LEE011): Mechanism of Action and Clinical Impact of This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors

Abstract

The cyclin D-cyclin-dependent kinase (CDK) 4/6-p16-retinoblastoma (Rb) pathway is commonly disrupted in cancer, leading to abnormal cell proliferation. Therapeutics targeting this pathway have demonstrated antitumor effects in preclinical and clinical studies. Ribociclib is a selective, orally bioavailable inhibitor of CDK4 and CDK6, which received FDA approval in March 2017 and is set to enter the treatment landscape alongside other CDK4/6 inhibitors, including palbociclib and abemaciclib. Here, we describe the mechanism of action of ribociclib and review preclinical and clinical data from phase I, II, and III trials of ribociclib across different tumor types, within the context of other selective CDK4/6 inhibitors. The pharmacokinetics, pharmacodynamics, safety, tolerability, and clinical responses with ribociclib as a single agent or in combination with other therapies are discussed, and an overview of the broad portfolio of ongoing clinical trials with ribociclib across a wide range of indications is presented. On the basis of the available data, ribociclib has a manageable tolerability profile and therapeutic potential for a variety of cancer types. Its high selectivity makes it an important partner drug for other targeted therapies, and it has been shown to enhance the clinical activity of existing anticancer therapies and delay the development of treatment resistance, without markedly increasing toxicity. Ongoing trials of doublet and triplet targeted therapies containing ribociclib seek to identify optimal CDK4/6-based targeted combination regimens for various tumor types and advance the field of precision therapeutics in oncology. Clin Cancer Res; 23(13); 3251-62. ©2017 AACR.

Figure 1

The role of cyclin–CDK complexes and the cyclin D–CDK4/6–p16–Rb pathway in the cell cycle The cell cycle is regulated by cyclins and checkpoints, with different cyclins (and cyclin–CDK combinations) and checkpoints acting at phase transition of the cell cycle. At the G1–S cell cycle checkpoint, mutiple mitogenic pathways including ER and PI3K/AKT/mTOR promote the synthesis of cyclin D, which associates with and activates CDK4/6. Activated CDK4/6 phosphorylates the Rb protein to disrupt its sequestering interaction with E2F, releasing its transcription effect and allowing the expression of genes necessary for cell cycle progression, including cyclin E. Cyclin E associates with CDK2, which further phosphorylates Rb, resulting in progression of the cell cycle past the restriction point and irreversible S phase entry. Additional cyclin–CDK complexes act at further cell cycle checkpoints; cyclin A–CDK2 enables the S–G2 transition, and cyclin A–CDK1 and cyclin B–CDK1 facilitate the onset and progression of mitosis, respectively (82). Selective inhibitors of CDK4/6, such as ribociclib, act directly on the cyclin D–CDK4/6–p16–Rb pathway to block cell cycle progression. The pathway may also be impacted by inhibitors of other pathways acting upstream of CDK4/6, providing a rationale for dual inhibition. CDK, cyclin-dependent kinase; ER, estrogen receptor; HER2, human epidermal growth factor receptor-2; IGF1R, insulin-like growth factor 1 receptor; MAPK, mitogen-activated protein kinase; RTK, receptor tyrosine kinase.