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.
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Acknowledgements
We thank N. Gray (Scripps Institute) for CDK inhibitors and helpful discussion, R. Longnecker (Northwestern Univ.) for the ES1 cell line and L. Urisman for excellent technical support. We thank G. Evan, K. Shannon, D. Donner and members of the Bishop and Morgan labs for helpful discussions. We thank the following for providing us with retroviral constructs: J. DeGregori (Univ. of Colorado) for E2F1 and E2F3, Y. Refaeli (National Jewish Medical and Research Center) for Myr-AKT and BCL2, O. Tetsu (Univ. California, San Francisco) for CCND1, O. Witte (Univ. California, Los Angeles) for BCR/ABL, and A. Capobianco (Univ. Pennsylvania) for Notch1-IC(ΔPest). We thank the University of California, San Francisco Liver Center (P30 DK26743) for procurement of normal mouse hepatocytes. This work was supported by a Howard Hughes Medical Institute Physician-Scientist Fellowship and US National Institutes of Health (NIH) K08 CA104032 (A.G.), The Susan G. Komen Breast Cancer Research Fund (D.Y.), NIH Medical Scientist Training Program (A.T.), NIH R01 GM69901 (D.M.) and the UCSF G.W. Hooper Research Foundation (J.M.B.).
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A.G. performed cell culture, biochemical experiments and histological analysis. A.G. and A.T. performed animal experiments. D.Y. performed siRNA experiments. A.G., D.O.M. and J.M.B. carried out experimental design, data analysis and manuscript preparation.
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Supplementary information
Supplementary Fig. 1
Preferential induction of apoptosis in MYC over-expressing RPE cells. (PDF 31 kb)
Supplementary Fig. 2
A MYC-dependent mouse liver cancer model. (PDF 390 kb)
Supplementary Fig. 3
Expression of oncogenes in Rat1 fibroblasts. (PDF 53 kb)
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Goga, A., Yang, D., Tward, A. et al. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat Med 13, 820–827 (2007). https://doi.org/10.1038/nm1606
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DOI: https://doi.org/10.1038/nm1606
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