The orderly progression of the cell cycle depends on the activation of CDK protein by binding to its cyclin partner. However, the cell cycle must be restricted when the cell undergoes abnormal changes. Most cancers correlate to the deregulated cell cycle, and since CDKs are a central component of the cell cycle, the CDK inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several CDKs, such as CDK 4/6, to form an active complex. The cyclin D-CDK4/6 complex then phosphorylates and inactivates the tumor suppressor retinoblastoma protein (Rb) to promote the G1-to-S phase transition of the cell cycle. In normal cells, Rb protein is reactivated through the regulation of CDK activity, thus, preventing abnormal cell cycle transitions.
There are at least three known mechanisms by which CDK activity is regulated- cyclin degradation, inhibitory phosphorylation, or binding of inhibitory proteins. Mutations that prevent these mechanisms lead to CDK-mediated tumorigenesis.
Because CDK 4/6 plays a substantial role in tumor formation, several CDK inhibitors have been developed for clinical use. The most recent ones are selective for CDK4 and CDK6. There are at least three clinically approved CDK 4/6 inhibitors: abemaciclib, ribociclib, and palbociclib. These inhibitors bind to the ATP pocket of CDK 4 and 6, inactivating the Cyclin D-CDK4/6 complexes, leading to Rb protein activation and subsequent cell cycle arrest. In some cases, the inhibitor-mediated cell cycle arrest causes an increase in apoptosis in tumor cells.
Inhibition of the cell cycle and subsequent programmed cell death are the most common mechanisms of CDK4/6 inhibitors. However, a recent study in mouse models of breast cancer showed that CDK4/6 inhibition could also lead to severe immunogenic effects. During the study, the CDK inhibitor seemed to enhance tumor cells' antigen-presenting ability, thereby allowing cytotoxic T cells to recognize and destroy the tumor cells.
Del capítulo 34:
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