Cyclin dependent kinases as targets for cancer therapy

The cell cycle represents a series of tightly integrated events that allow the cell to grow and proliferate. Critical parts of the cell cycle machinery are the cyclin dependent kinases (CDKs) which, when activated, provide a means for the cell to move from one phase of the cell cycle to the next. The CDKs are positively regulated by cyclins and negatively regulated by naturally occurring cyclin dependent kinase inhibitors (CDKIs). Cancer represents a dysregulation of the cell cycle such that cells that over-express cyclins or do not express the CDKIs continue to undergo unregulated cell growth. The cell cycle also serves to protect the cell from DNA damage. Thus, cell cycle arrest represents a survival mechanism that provides the tumor cell the opportunity to repair damaged DNA. Abrogation of cell cycle checkpoints before DNA repair is complete can activate the apoptotic cascade leading to cell death. Over the past several years a series of targeted agents have been developed that directly inhibit the CDKs, inhibit unrestricted cell growth, and induce a growth arrest. In addition, there are now agents that abrogate the cell cycle checkpoints at critical time points and make the tumor cell susceptible to apoptosis. Many of these agents are now in clinical trials and represent a new direction in cancer treatment. An understanding of the cell cycle is critical to learning how best to clinically develop these agents, both when administered as single agents or in combination with chemotherapy.