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Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC

Nature Medicine volume 13, pages 820–827 (2007)Cite this article

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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Figure 1: CDK1 inhibition causes G2 arrest in fibroblasts and human cells.
Figure 2: Survey of human oncogenes and cell lines reveals preferential cell death of MYC-overexpressing cells after purvalanol treatment.
Figure 3: Cells with temperature-sensitive Cdk1 are sensitive to MYC overexpression at the nonpermissive temperature.
Figure 4: MYC-dependent tumors are sensitive to CDK1 inhibition.
Figure 5: Treatment with purvalanol induces apoptosis of MYC-driven liver tumors.
Figure 6: Depletion of survivin selectively kills MYC overexpressing cells.

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References

  1. Morgan, D.O. The Cell Cycle: Principles of Control (New Science Press, London, 2007).

    Google Scholar 

  2. Th'ng, J.P. et al. The FT210 cell line is a mouse G2 phase mutant with a temperature-sensitive CDC2 gene product. Cell 63, 313–324 (1990).

    Article  CAS  Google Scholar 

  3. Itzhaki, J.E., Gilbert, C.S. & Porter, A.C. Construction by gene targeting in human cells of a 'conditional' CDC2 mutant that rereplicates its DNA. Nat. Genet. 15, 258–265 (1997).

    Article  CAS  Google Scholar 

  4. Morgan, D.O. Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu. Rev. Cell Dev. Biol. 13, 261–291 (1997).

    Article  CAS  Google Scholar 

  5. Gray, N.S. et al. Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science 281, 533–538 (1998).

    Article  CAS  Google Scholar 

  6. O'Connor, D.S. et al. Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc. Natl. Acad. Sci. USA 97, 13103–13107 (2000).

    Article  CAS  Google Scholar 

  7. Jiang, X.R. et al. Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype. Nat. Genet. 21, 111–114 (1999).

    Article  CAS  Google Scholar 

  8. Van Roy, F.M. et al. Invasiveness and metastatic capability of rat fibroblast-like cells before and after transfection with immortalizing and transforming genes. Cancer Res. 46, 4787–4795 (1986).

    CAS  PubMed  Google Scholar 

  9. Klefstrom, J., Verschuren, E.W. & Evan, G. c-Myc augments the apoptotic activity of cytosolic death receptor signaling proteins by engaging the mitochondrial apoptotic pathway. J. Biol. Chem. 277, 43224–43232 (2002).

    Article  CAS  Google Scholar 

  10. Juin, P., Hueber, A.O., Littlewood, T. & Evan, G. c-Myc-induced sensitization to apoptosis is mediated through cytochrome c release. Genes Dev. 13, 1367–1381 (1999).

    Article  CAS  Google Scholar 

  11. Davenport, E.A., Drobes, B.L., Menke, S.L., Vaidya, T.B. & Taparowsky, E.J. Cooperation of oncogenes in the multistep transformation of established fibroblasts in culture. Anticancer Res. 8, 959–969 (1988).

    CAS  PubMed  Google Scholar 

  12. Eischen, C.M., Weber, J.D., Roussel, M.F., Sherr, C.J. & Cleveland, J.L. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev. 13, 2658–2669 (1999).

    Article  CAS  Google Scholar 

  13. Zindy, F. et al. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 12, 2424–2433 (1998).

    Article  CAS  Google Scholar 

  14. Little, C.D., Nau, M.M., Carney, D.N., Gazdar, A.F. & Minna, J.D. Amplification and expression of the c-myc oncogene in human lung cancer cell lines. Nature 306, 194–196 (1983).

    Article  CAS  Google Scholar 

  15. Hollis, G.F., Gazdar, A.F., Bertness, V. & Kirsch, I.R. Complex translocation disrupts c-myc regulation in a human plasma cell myeloma. Mol. Cell. Biol. 8, 124–129 (1988).

    Article  CAS  Google Scholar 

  16. Mineo, C., Murakami, Y., Ishimi, Y., Hanaoka, F. & Yamada, M. Isolation and analysis of a mammalian temperature-sensitive mutant defective in G2 functions. Exp. Cell Res. 167, 53–62 (1986).

    Article  CAS  Google Scholar 

  17. Adams, J.M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985).

    Article  CAS  Google Scholar 

  18. Shachaf, C.M. et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature 431, 1112–1117 (2004).

    Article  CAS  Google Scholar 

  19. Green, D.R. & Evan, G.I. A matter of life and death. Cancer Cell 1, 19–30 (2002).

    Article  CAS  Google Scholar 

  20. Deveraux, Q.L. et al. IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 17, 2215–2223 (1998).

    Article  CAS  Google Scholar 

  21. Roy, N., Deveraux, Q.L., Takahashi, R., Salvesen, G.S. & Reed, J.C. The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J. 16, 6914–6925 (1997).

    Article  CAS  Google Scholar 

  22. Mesri, M., Wall, N.R., Li, J., Kim, R.W. & Altieri, D.C. Cancer gene therapy using a survivin mutant adenovirus. J. Clin. Invest. 108, 981–990 (2001).

    Article  CAS  Google Scholar 

  23. Beltrami, E., Plescia, J., Wilkinson, J.C., Duckett, C.S. & Altieri, D.C. Acute ablation of survivin uncovers p53-dependent mitotic checkpoint functions and control of mitochondrial apoptosis. J. Biol. Chem. 279, 2077–2084 (2004).

    Article  CAS  Google Scholar 

  24. Mateyak, M.K., Obaya, A.J. & Sedivy, J.M. c-Myc regulates cyclin D-Cdk4 and -Cdk6 activity but affects cell cycle progression at multiple independent points. Mol. Cell. Biol. 19, 4672–4683 (1999).

    Article  CAS  Google Scholar 

  25. Beier, R. et al. Induction of cyclin E-cdk2 kinase activity, E2F-dependent transcription and cell growth by Myc are genetically separable events. EMBO J. 19, 5813–5823 (2000).

    Article  CAS  Google Scholar 

  26. Schuldiner, O. & Benvenisty, N.A. DNA microarray screen for genes involved in c-MYC and N-MYC oncogenesis in human tumors. Oncogene 20, 4984–4994 (2001).

    Article  CAS  Google Scholar 

  27. Swarbrick, A. et al. Regulation of cyclin expression and cell cycle progression in breast epithelial cells by the helix-loop-helix protein Id1. Oncogene 24, 381–389 (2005).

    Article  CAS  Google Scholar 

  28. Afar, D.E., Goga, A., McLaughlin, J., Witte, O.N. & Sawyers, C.L. Differential complementation of Bcr-Abl point mutants with c-Myc. Science 264, 424–426 (1994).

    Article  CAS  Google Scholar 

  29. Sofer-Levi, Y. & Resnitzky, D. Apoptosis induced by ectopic expression of cyclin D1 but not cyclin E. Oncogene 13, 2431–2437 (1996).

    CAS  PubMed  Google Scholar 

  30. Shan, B., Farmer, A.A. & Lee, W.H. The molecular basis of E2F–1/DP-1-induced S-phase entry and apoptosis. Cell Growth Differ. 7, 689–697 (1996).

    CAS  PubMed  Google Scholar 

  31. Nesbit, C.E., Grove, L.E., Yin, X. & Prochownik, E.V. Differential apoptotic behaviors of c-myc, N-myc, and L-myc oncoproteins. Cell Growth Differ. 9, 731–741 (1998).

    CAS  PubMed  Google Scholar 

  32. Adachi, S. et al. c-Myc is necessary for DNA damage-induced apoptosis in the G(2) phase of the cell cycle. Mol. Cell. Biol. 21, 4929–4937 (2001).

    Article  CAS  Google Scholar 

  33. O'Connor, D.S., Wall, N.R., Porter, A.C. & Altieri, D.C. A p34(cdc2) survival checkpoint in cancer. Cancer Cell 2, 43–54 (2002).

    Article  CAS  Google Scholar 

  34. Altieri, D.C. The case for survivin as a regulator of microtubule dynamics and cell-death decisions. Curr. Opin. Cell Biol. 18, 609–615 (2006).

    Article  CAS  Google Scholar 

  35. Blanc-Brude, O.P. et al. Therapeutic targeting of the survivin pathway in cancer: initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis. Clin. Cancer Res. 9, 2683–2692 (2003).

    CAS  PubMed  Google Scholar 

  36. Plescia, J. et al. Rational design of shepherdin, a novel anticancer agent. Cancer Cell 7, 457–468 (2005).

    Article  CAS  Google Scholar 

  37. Bild, A.H. et al. Oncogenic pathway signatures in human cancers as a guide to targeted therapies. Nature 439, 353–357 (2006).

    Article  CAS  Google Scholar 

  38. Pear, W.S., Nolan, G.P., Scott, M.L. & Baltimore, D. Production of high-titer helper-free retroviruses by transient transfection. Proc. Natl. Acad. Sci. USA 90, 8392–8396 (1993).

    Article  CAS  Google Scholar 

  39. Eilers, M., Picard, D., Yamamoto, K.R. & Bishop, J.M. Chimaeras of myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells. Nature 340, 66–68 (1989).

    Article  CAS  Google Scholar 

  40. Hirose, Y., Berger, M.S. & Pieper, R.O. Abrogation of the Chk1-mediated G2 checkpoint pathway potentiates temozolomide-induced toxicity in a p53-independent manner in human glioblastoma cells. Cancer Res. 61, 5843–5849 (2001).

    CAS  PubMed  Google Scholar 

  41. Felsher, D.W. & Bishop, J.M. Reversible tumorigenesis by MYC in hematopoietic lineages. Mol. Cell 4, 199–207 (1999).

    Article  CAS  Google Scholar 

  42. Yang, D., Welm, A. & Bishop, J.M. Cell division and cell survival in the absence of survivin. Proc. Natl. Acad. Sci. USA 101, 15100–15105 (2004).

    Article  CAS  Google Scholar 

Download references

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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Authors and Affiliations

  1. Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, San Francisco, 94143-0552, California, USA

    Andrei Goga

  2. Department of Physiology, University of California, San Francisco, San Francisco, 94143-0552, California, USA

    David O Morgan

  3. Department of Microbiology and Immunology and George Williams Hooper Foundation, University of California, San Francisco, San Francisco, 94143-0552, California, USA

    Andrei Goga, Dun Yang, Aaron D Tward & J Michael Bishop

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  1. Andrei Goga
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Contributions

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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Correspondence to Andrei Goga.

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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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