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 was granted priority review by the US Food and Drug Administration in November 2016, 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. Based on 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.

Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer

“…Both palbociclib and ribociclib have >100-fold higher affinity for CDK4 and CDK6 relative to other cell cycle CDKs and CDK9 . In contrast, abemaciclib is less selective, with only ~six-fold higher affinity for CDK4/6 than it has for CDK9 and has some activity towards CDK1, CDK2 and CDK5 at higher doses (Gelbert et al 2014, Tripathy et al 2017 (Table 1). Despite being less selective, in a direct comparison, abemaciclib was found to more efficiently pass through the blood-brain barrier than palbociclib (Raub et al 2015), which widens its potential application to brain cancers and secondary brain metastases (NCT02308020).…”

“…Early preclinical breast cancer studies demonstrated that palbociclib preferentially inhibited the proliferation of ER+ in contrast to ER− breast cancer models in vitro Palbociclib (Fry et al 2004) Ribociclib (Tripathy et al 2017) Abemaciclib (Gelbert et al 2014) IC 50 (nmol/L) CDK4-cyclin D1/D3…”

Ebola Virus VP40 Modulates Cell Cycle and Biogenesis of Extracellular Vesicles

“…The indication that 293T cells react to both cdk4/6 inhibitors in a similar way, but V2CH cells do not, hints that these drugs may impact cell cycle regulation and EV biogenesis pathways in distinctly different ways. Although the mechanism of action for Fascaplysin is currently uncharacterized, Ribociclib is known to interact directly with cdk4 and cdk6 molecules at their ATP pocket [84,85]. Future study into the divergent mechanisms used by these drugs and how they may interact with pathways modulated by VP40 may potentially be advantageous to determine the potential therapeutic utility of cdk4/6 inhibitors in infection.…”

Pathogenesis and Clinical Management of Uterine Serous Carcinoma

“…Four generations of cyclin-dependent kinase (CDK) inhibitors have been synthetized, and some are under clinical investigation in patients with EC. For example, a phase I study of ribociclib (LEE011), a selective inhibitor of CDK4/6, demonstrated an acceptable safety profile and preliminary antitumor activity in patients with advanced tumors including EC [108]. A trial of combined treatment with ribociclib, everolimus, and letrozole in patients with advanced or recurrent EC is still recruiting (NCT03008408).…”