Cyclin-dependent kinases (cdks) and the DNA damage response: rationale for cdk inhibitor-chemotherapy combinations as an anticancer strategy for solid tumors.

摘要

IMPORTANCE OF THE FIELD: The eukaryotic cell division cycle is a tightly regulated series of events coordinated by the periodic activation of multiple cyclin-dependent kinases (cdks). Small-molecule cdk-inhibitory compounds have demonstrated preclinical synergism with DNA-damaging agents in solid tumor models. An improved understanding of how cdks regulate the DNA damage response now provides an opportunity for optimization of combinations of cdk inhibitors and DNA damaging chemotherapy agents that can be translated to clinical settings. AREAS COVERED IN THIS REVIEW: Here, we discuss novel work uncovering multiple roles for cdks in the DNA-damage-response network. First, they activate DNA damage checkpoint and repair pathways. Later their activity is turned off, resulting in cell cycle arrest, allowing time for DNA repair to occur. Recent clinical data on cdk inhibitor-DNA-damaging agent combinations are also discussed. WHAT THE READER WILL GAIN: Readers will learn about novel areas of cdk biology, the complexity of DNA damage signaling networks and clinical implications. TAKE HOME MESSAGE: New data demonstrate that cdks are 'master' regulators of DNA damage checkpoint and repair pathways. Cdk inhibition may therefore provide a means of potentiating the clinical activity of DNA-damaging chemotherapeutic agents for the treatment of cancer.