The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer

Abstract

Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation through regulating cell-cycle checkpoints and transcriptional events in response to extracellular and intracellular signals. Not surprisingly, the dysregulation of CDKs is a hallmark of cancers, and inhibition of specific members is considered an attractive target in cancer therapy. In breast cancer (BC), dual CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib, combined with other agents, were approved by the Food and Drug Administration (FDA) recently for the treatment of hormone receptor positive (HR+) advanced or metastatic breast cancer (A/MBC), as well as other sub-types of breast cancer. Furthermore, ongoing studies identified more selective CDK inhibitors as promising clinical targets. In this review, we focus on the roles of CDKs in driving cell-cycle progression, cell-cycle checkpoints, and transcriptional regulation, a highlight of dysregulated CDK activation in BC. We also discuss the most relevant CDK inhibitors currently in clinical BC trials, with special emphasis on CDK4/6 inhibitors used for the treatment of estrogen receptor-positive (ER+)/human epidermal growth factor 2-negative (HER2−) M/ABC patients, as well as more emerging precise therapeutic strategies, such as combination therapies and microRNA (miRNA) therapy.

Discovery of 3,6-disubstituted pyridazines as a novel class of anticancer agents targeting cyclin-dependent kinase 2: synthesis, biological evaluation and in silico insights

“…In particular, CDK2 is listed as one of the top suggested kinases. It is interesting to note that the suggestion of CDK2 as a potential target is perfectly tuned with its known expression in breast cancer 37 , and with the obtained results from the cell cycle analysis, as the role of CDK2 in the cell cycle is well-established 3 . Accordingly, a molecular docking work was conducted in order to examine the plausible binding modes and interactions of the target pyridazines 11a-r within the active site of CDK2.…”

Up-regulation of FN1, Activation of Maturation Promoting Factor and Associated Signaling Pathway Facilitates Epithelial-Mesenchymal Transition, Inhibits Apoptosis and Elevates Proliferation Rate of Breast Cancer Cells: In Silico Analysis of Microarray Datasets

“…The downregulation of CDK1 has been associated with breast cancer by Lie Ding et al [28]. Moreover, Lie Ding et al [28] also reported that breast cancer patients with overexpression of CDK1 and CDK2 had signi cantly poorer OS compared to those with low CDK1 and CDK2 expression. Similar role of CDKs has also been reported in renal cell carcinoma [29].…”

“…The cell cycle dysregulation is the major event that occurs in cancer cells [26] and Cyclin-dependent kinases (CDKs) are the well-known proteins involved in the regulation of cell cycle [27]. The downregulation of CDK1 has been associated with breast cancer by Lie Ding et al [28]. Moreover, Lie Ding et al [28] also reported that breast cancer patients with overexpression of CDK1 and CDK2 had signi cantly poorer OS compared to those with low CDK1 and CDK2 expression.…”

Significance of Targeting VEGFR-2 and Cyclin D1 in Luminal-A Breast Cancer

“…The ATP-competitive inhibitor, dinaciclib, exhibited IC 50 sub 4 nM against a broad spectrum of CDKs (1, 2, 5, and 9) and RB phosphorylation in BC cell lines, simultaneously with induction of apoptosis, all of which was better compared to flavopiridol. It was also reported that the combination of dinaciclib with an anthracycline showed synergism in BC cell lines [ 38 ]. It also showed encouraging efficacy, safety, and tolerability profiles as a monotherapy in a clinical trial phase II for advanced BC, which involved ER + /Her2 - patients.…”