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.

Keywords: CDK inhibitor; breast cancer (BC); cell cycle; clinic therapy; cyclin-dependent kinase (CDK).

Figure 1

Progression of the cell cycle and its regulation by the CDKs and checkpoints. The cell cycle is regulated by many CDKs which form complexes with their associated cyclin partners. The cell cycle consists of four distinct ordered phases of the cell cycle, termed G0/G1, S, G2, and M phases, and it contains multiple checkpoints (red) throughout to prevent genomic instability, as well as ensure faithful replication. The cells exit the cell cycle and enter the reversible or permanent quiescent state (G0 phase) regulated by cyclin C/CDK3. Various extracellular signals, such as the mitogenic signal, lead to the synthesis of cyclin D and stimulate CDK4/6, resulting in promoting entry into the cell cycle. Active CDK4/6 complexes initiate the phosphorylation (P) of RB protein, thereby unleashing E2F transcription factors, resulting in the expression of cyclin E, cyclin A, cyclin B, and many genes required for S phase progression. Cyclin E subsequently activates CDK2 and contributes to the further phosphorylating RB, progresses into S phase, and initiates DNA synthesis. Near the end of S phase, cyclin A removes cyclin E and forms a new complex, cyclin A/CDK2. Cyclin A/CDK2 terminates the S phase by phosphorylating CDC6 and E2F1; it drives the cell-cycle transition from S phase to G2 phase, and subsequently activates CDK1 by cyclin A, leading to cells entering the M phase. Upon mitosis, the CDK1 activity is maintained by the complex cyclin B/CDK1. The deregulation of CDK1 enables chromosome separation and the completion of mitosis and cytokinesis. The INK4, CIP/KIP, and CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) inhibit the activity of CDK/cyclin. The ubiquitination (Ub) of cyclins is involved in regulating the expression of many proteins to control the cyclical activities of the CDKs, such as SCF and APC/C. The PLK1 and aurora A proteins are involved in the progression through S phase and from G2 phase into M phase. In addition, DNA damage checkpoints safeguard the genomic integrity and trigger cell-cycle arrest via checkpoint kinase 2 (CHK2) and p53 in G1 phase or via CHK1 in S or G2 phase. P in a dashed circle shows dephosphorylation. Green ovals indicate positive regulators and blue ovals indicate negative regulators of cell-cycle progression. (Adapted from reference “[8], doi:10.1038/nrc.2016.138” with permission of the journal Nature Reviews Cancer 2017).

Figure 2

CDK/cyclin complexes regulate the RNAPII-based transcription cycle of pre-initiation, initiation, elongation, and termination. CDK8/19 activates the transcription machinery at the promoter level. CDK8/19 also phosphorylates cyclin H to inhibit the assembly of the PIC to negatively regulate the activity of TFIIH, and it phosphorylates the CTD of RNAPII to impede its binding to promoter DNA and to inhibit the assembly of the PIC. CDK7 and CDK9 drive mRNA elongation via sequential phosphorylation of the CTD-RNAPII. CDK12 and CDK13 with their cofactor cyclin K are also responsible for Ser2 phosphorylation at the CTD, allowing mRNA elongation. CDK11 is involved in the coordination between transcription and RNA splicing. DSIF and NELF inhibit elongation, while SCP1 promotes the termination of transcription. (Adapted from reference “[42], doi:10.1242/dev.091744” with permission of the journal Development 2013).