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Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment

Geoffrey I. Shapiro

From the Department of Medical Oncology, Dana-Farber Cancer Institute; and the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA

Address reprint requests to Geoffrey I. Shapiro, MD, PhD, Dana Farber Cancer Institute, Dana 810A, 44 Binney St, Boston, MA 02115; e-mail: geoffrey_shapiro{at}dfci.harvard.edu

Cyclin-dependent kinases (cdks) are critical regulators of cell cycle progression and RNA transcription. A variety of genetic and epigenetic events cause universal overactivity of the cell cycle cdks in human cancer, and their inhibition can lead to both cell cycle arrest and apoptosis. However, built-in redundancy may limit the effects of highly selective cdk inhibition. Cdk4/6 inhibition has been shown to induce potent G₁ arrest in vitro and tumor regression in vivo; cdk2/1 inhibition has the most potent effects during the S and G₂ phases and induces E2F transcription factor–dependent cell death. Modulation of cdk2 and cdk1 activities also affects survival checkpoint responses after exposure to DNA-damaging and microtubule-stabilizing agents. The transcriptional cdks phosphorylate the carboxy-terminal domain of RNA polymerase II, facilitating efficient transcriptional initiation and elongation. Inhibition of these cdks primarily affects the accumulation of transcripts with short half-lives, including those encoding antiapoptosis family members, cell cycle regulators, as well as p53 and nuclear factor-kappa B–responsive gene targets. These effects may account for apoptosis induced by cdk9 inhibitors, especially in malignant hematopoietic cells, and may also potentiate cytotoxicity mediated by disruption of a variety of pathways in many transformed cell types. Current work is focusing on overcoming pharmacokinetic barriers that hindered development of flavopiridol, a pan-cdk inhibitor, as well as assessing novel classes of compounds potently targeting groups of cell cycle cdks (cdk4/6 or cdk2/1) with variable effects on the transcriptional cdks 7 and 9. These efforts will establish whether the strategy of cdk inhibition is able to produce therapeutic benefit in the majority of human tumors.

Supported by Grant No. R01 CA90687 and the Dana-Farber/Harvard Cancer Center Specialized Program of Research Excellence (SPORE) in Lung Cancer Grant No. P20 CA90578 from the National Institutes of Health, and by a Mantle Cell Lymphoma Research Grant from the Lymphoma Research Foundation.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Author's disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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