Recent advances of cyclin-dependent kinases as potential therapeutic targets in HR+/HER2− metastatic breast cancer: a focus on ribociclib

Breast Cancer - Targets and Therapy Dovepress open access to scientific and medical research Review Breast Cancer: Targets and Therapy downloaded from https://www.dovepress.com/ by 213.32.59.121 on 12-Jul-2018 For personal use only. Open Access Full Text Article Recent advances of cyclin-dependent kinases as potential therapeutic targets in HR+/HER2− metastatic breast cancer: a focus on ribociclib This article was published in the following Dove Press journal: Breast Cancer - Targets and Therapy Dumessa Edessa 1 Mekonnen Sisay 2 Department of Pharmacy Practice, Department of Pharmacology and Toxicology, School of Pharmacy, College of Health and Medical Sciences, Haramaya University, Oromia, Ethiopia 1 2 Abstract: In normal cell cycle progression, transition of G0/G1 phase to synthesis (S) phase for breast and other cells is regulated by association of cyclin D and cyclin-dependent kinases 4 and 6 (CDK4/6) that leads to phosphorylation of retinoblastoma (Rb) protein. Imbalance of this cyclin D-CDK4/6-inhibitors of CDK4/6-Rb phosphorylation pathway is associated with tumorigenesis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2−) breast cancers. Despite effective first-line endocrine therapy, HR+/ HER2− metastatic breast cancers remain still incurable. Currently, advances in understanding of cell cycle checkpoints are evolving as promising strategy to target in treatment of various types of cancers including breast cancer. Therapies that target this cell cycle machinery in HR+/ HER2− breast cancers are getting approval by the US Food and Drug administration (FDA) including ribociclib (LEE011). Ribociclib got the first FDA approval in March 13, 2017, as an initial therapy for HR+/HER2− advanced or metastatic breast cancer in combination with an aromatase inhibitor. This review, therefore, addresses the role of selective CDK4/6 inhibitors in advanced or metastatic breast cancer with a specific focus on ribociclib. Some findings of clinical trials involving ribociclib found pivotal benefits of ribociclib in HR+/HER2− metastatic breast cancer in terms of prolonging progression-free survival and objective response rates. Daily dosage range of the drug for such benefits is 50–900 mg with common daily doses of 400 or 600 mg and 600 mg in early and advanced breast cancer therapies, respectively. Along with its therapeutic benefits, however, more incident but manageable dose-limiting grade 3 or 4 toxicities, primarily hematologic adverse events, are common in patients treated with ribociclib. Generally, there are several active clinical trials undergoing to investigate the clinical efficacy and toxicity profile of the drug in various cancerous conditions other than breast cancer and will likely benefit patients with other cancer types. Keywords: cell cycle, cyclin-dependent kinase 4/6, HR+/HER2−, metastatic breast cancer, CDK4/6 inhibitors, ribociclib, LEE011 Introduction Overview of cell cycle pathways and cyclins/cyclindependent kinases Correspondence: Dumessa Edessa Department of Pharmacy Practice, School of Pharmacy, College of Health and Medical Sciences, Haramaya University, P.O. Box, 235, Oromia, Ethiopia Tel +251 2 5667 1466 Fax +251 2 5666 8081 Email To keep homeostasis, cellular multiplication processes and associated programmed cell death (apoptosis) need to be regulated. However, improper signal passed on to cell cycle regulators (e.g., cyclins, cyclin-dependent kinases [CDKs], and endogenous CDK inhibitors) as a result of mutation and other related factors is associated with tumorigenesis of many cancers1–5 including breast cancer.2 This means that normal cyclins and CDKs are deregulated and/or apoptosis is inappropriately regulated in the submit your manuscript | www.dovepress.com Breast Cancer - Targets and Therapy 2017:9 567–579 Dovepress © 2017 Edessa and Sisay. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). http://dx.doi.org/10.2147/BCTT.S150540 Powered by TCPDF (www.tcpdf.org) 567 Dovepress Breast Cancer: Targets and Therapy downloaded from https://www.dovepress.com/ by 213.32.59.121 on 12-Jul-2018 For personal use only. Edessa and Sisay cancers accounting for unrestrained cellular duplication as hallmark of cancer cells.4,6–8 Therefore, understanding the normal cellular progression and development machineries is critical to effective or targeted treatment of cancers including breast cancer. Majority of normal human cells reside in a detained cell cycle state called G0 phase.8,9 The detained state can be either transient or permanent. The transient (G0 phase) cells can be potentiated to reenter the cell cycle by various factors that include CDKs and their respective regulatory subunits called cyclins.1,4,8,9 More specifically, most of the factors, through activation of cascades of intracellular signaling pathways, cause CDK4 and CDK6 to instigate the cell cycle progression from G0/G1 transition state to synthesis (S) phase.9 In G1 phase, association of cyclin D with CDK4 and/or CDK6 forms a complex that results in the activation of CDK4/6.10–12 In turn, the activated complex of cyclin-CDK4/6 can phosphorylate a signaling protein called retinoblastoma (Rb).8,10 The later process leads to dictation of genes required for G1/S transition and move on to cell cycle progression.10 At this stage, targeted inhibition of the regulators of G1/S transition checkpoint can arrest the cellular cycle from progressing to S phase.13 Likewise, the necessary instigation for cellular progression form G1/S transition and S phase of cell cycle to subsequent phases is regulated by cyclin E-CDK2 and cyclin A-CDK2, respectively. Similar pathways occur at G2 and mitosis (M) phases being regulated by cyclin A-CDK1 and cyclin B-CDK1, respectively.4,8,10 For more detail understanding, the aforementioned descriptions of cellular processes and regulatory pathways are clearly portrayed in Figure 1. In normal cells, the activities of CDKs are controlled positively by associating primarily with the “D cyclins” (D1, D2, and D3) and ‘cyclins A, B, and E’; this move on pathways are blocked by endogenous inhibitors of CDK (INK) such as p16INK4A, p15INKB, p18INK4C, and p19INK4D family proteins.9 Moreover, besides the regulation of cell cycle progression, CDKs in the presence of their respective cyclins can form families of heterodimeric kinases, which play pivotal (...truncated)