The role of cyclin–CDK complexes and the cyclin D–CDK4/6–p16–Rb pathway in the cell cycle. The tumor suppressor and negative regulator of the cyclin D–CDK4/6 complex, p16, is a critical mediator of cellular senescence, limiting the replicative life span of cells ( 7). The released E2F consequently activates the transcription of genes required for the G 1–S transition and cell-cycle progression ( 5, 6). The resulting active cyclin D–CDK4/6 complexes phosphorylate Rb, relieving its repression of E2 transcription factors (E2F). In response to mitogenic signaling, levels of D-type cyclins rise and associate with CDK4 or CDK6. In this pathway, cyclin D is the key entry point at which various mitogenic and growth arrest signaling pathways converge to regulate the cell cycle ( 3). The G 1 (pre-DNA synthesis) to S (DNA synthesis) cell-cycle checkpoint is regulated by the cyclin D–CDK4/6–p16–retinoblastoma (Rb) pathway, which ensures conditions are appropriate for cell growth and division before the cell is irreversibly committed to division ( 2–4). The cell cycle is regulated at different stages by various cyclin–cyclin-dependent kinase (CDK) complexes ( Fig. ©2017 AACR.Ĭancer development is often characterized by abnormal cellular proliferation and dysregulation of cell-cycle control ( 1). 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. 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. On the basis of the available data, ribociclib has a manageable tolerability profile and therapeutic potential for a variety of cancer types. 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. 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. 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. Therapeutics targeting this pathway have demonstrated antitumor effects in preclinical and clinical studies. The cyclin D–cyclin-dependent kinase (CDK) 4/6–p16–retinoblastoma (Rb) pathway is commonly disrupted in cancer, leading to abnormal cell proliferation.
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