As gatekeepers of the cell cycle, the cyclin-dependent kinases are often implicated in the progression of cancer and make prime targets for therapy. Mirroring the cellular process that they target, two decades of CDK inhibitor development has cycled through excitement to disappointment, back to potential success.
Dual inhibitors of CDK4/6 are showing particular promise for the treatment of advanced breast cancer, and several agents are vying for success in the late stages of clinical development. Meanwhile, a pan-CDK inhibitor, dinaciclib, has worked its way through to phase III in chronic lymphocytic leukemia (CLL).
The translation of phase II success stories into the final stages of clinical development is eagerly anticipated, and it seems the stage may finally be set for approval of a CDK inhibitor for anticancer therapy.
Cyclin-Dependent Kinases: Gatekeepers of the Cell Cycle
The cell cycle is a highly regulated series of steps that takes the cell from a noncycling, quiescent state (G0) through an initial growth phase (G1), which is a regulatory and preparatory period leading up to a period of DNA replication (S), followed by a second growth phase (G2), involving rapid growth and protein synthesis, and ending in mitosis (Figure 1), during which the genetic material is condensed into chromosomes and divided equally into two genetically identical daughter cells (Figure 2).
Figure 1. How CDK4/6 Influences the Cell Cycle
CDK4/6 indicates cyclin-dependent kinases 4 and 6; E2F, transcription factors of E2F gene; G, growth phases, M, mitosis; RB, retinoblastoma protein; S, DNA replication.
Progression through the cell cycle is controlled by a wealth of specific cell cycle-associated proteins that act as “gatekeepers,” ensuring that the transition between the distinct phases of the cell cycle occur only at the appropriate time.
One particularly important group of gatekeeper proteins are the cyclin-dependent kinases (CDKs). The human genome encodes 21 CDKs, although only 7 (CDK1, 2, 3, 4, 6, 10, and 11) have been shown to have a direct role in the cell cycle. Other CDKs play an indirect, though no less important, role via activation of fellow CDKs or regulation of transcription.
The activity of CDKs is meticulously regulated via a number of activating and inhibitory mechanisms, but primarily through binding to cyclins. Cyclins were originally named for the cycling of their activity over the course of the cell cycle in response to growth signals in the cellular environment, which occurs in a distinct pattern for each cyclin.
Figure 2. Process of Mitosis in Normal Cells
In the process of mitosis, chromosomes replicate and produce two identical nuclei in preparation for cell division. Aberrant CDK4/6 activity ultimately dysregulates mytosis. Courtesy of the National Human Genome Research Institute. “Talking Glossary of Genetic Terms.”
The best-known and most important cyclins in cell cycle transitions are cyclins A, B, D, and E. D-type cyclins, partnered with CDK4 and CDK6, function in mid-to-late G1 and, in concert with cyclin E/CDK2, primarily regulate the G1—S transition. Cyclin A activates CDK1 and CDK2 in S phase and regulates the S/G2 transition, and the B-type cyclins, particularly cyclin B1 partnered with CDK1, drive entry into mitosis.
The transition from G1—S phase is particularly important as it is at this point that the cell commits to entering the cell cycle—the so-called restriction point, beyond which cells proceed into S phase regardless of external stimuli. The cyclin D-dependent kinases CDK4 and CDK6, as well as cyclin E/CDK2, are the primary regulators of this transition through activation of downstream signaling components. It is now appreciated that an array of downstream targets are activated and that there is significant crosstalk between them, such that CDK4/6 forms a central node in a complex network of signaling pathways. However, the best-characterized downstream target is the retinoblastoma protein (pRB).
pRB forms multiprotein complexes with a variety of other signaling proteins, including the E2F transcription factors, which it maintains in an inactive state. Cyclin D activates CDK4/6, which phosphorylates pRB and removes the repression of E2F transcription factors. This activates transcription of E2F target genes, which include many that are important for G1—S transition, ultimately pushing the cell past the restriction point.