Article abstract
Nature Medicine 13, 820 - 827 (2007)
Published online: 24 June 2007 | doi:10.1038/nm1606
Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC
Andrei Goga1,3, Dun Yang3, Aaron D Tward3, David O Morgan2 & J Michael Bishop3
Abstract
Tumor cells have a dysregulated cell cycle that may render their proliferation especially sensitive to the inhibition of cyclin-dependent kinases (CDKs), important regulators of cell cycle progression. We examined the effects of CDK1 inhibition in the context of different oncogenic signals. Cells transformed with MYC, but not cells transformed by a panel of other activated oncogenes, rapidly underwent apoptosis when treated with small-molecule CDK1 inhibitors. The inhibitor of apoptosis protein BIRC5 (survivin), a known CDK1 target, is required for the survival of cells overexpressing MYC. Inhibition of CDK1 rapidly downregulates survivin expression and induces MYC-dependent apoptosis. CDK1 inhibitor treatment of MYC-dependent mouse lymphoma and hepatoblastoma tumors decreased tumor growth and prolonged their survival. As there are no effective small-molecule inhibitors that selectively target the MYC pathway, we propose that CDK1 inhibition might therefore be useful in the treatment of human malignancies that overexpress MYC.
- Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California 94143-0552, USA.
- Department of Physiology, University of California, San Francisco, San Francisco, California 94143-0552, USA.
- Department of Microbiology and Immunology and George Williams Hooper Foundation, University of California, San Francisco, San Francisco, California 94143-0552, USA.
Correspondence to: Andrei Goga1,3 e-mail: andrei.goga@ucsf.edu
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