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Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors

Nature Structural & Molecular Biology volume 18, pages 1331–1335 (2011)Cite this article

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Abstract

Oncogene-induced replicative stress activates an Atr- and Chk1-dependent response, which has been proposed to be widespread in tumors. We explored whether the presence of replicative stress could be exploited for the selective elimination of cancer cells. To this end, we evaluated the impact of targeting the replicative stress-response on cancer development. In mice (Mus musculus), the reduced levels of Atr found on a mouse model of the Atr-Seckel syndrome completely prevented the development of Myc-induced lymphomas or pancreatic tumors, both of which showed abundant levels of replicative stress. Moreover, Chk1 inhibitors were highly effective in killing Myc-driven lymphomas. By contrast, pancreatic adenocarcinomas initiated by K-RasG12V showed no detectable evidence of replicative stress and were nonresponsive to this therapy. Besides its impact on cancer, Myc overexpression aggravated the phenotypes of Atr-Seckel mice, revealing that oncogenes can modulate the severity of replicative stress-associated diseases.

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Figure 1: Reduced levels of Atr prevent lymphomagenesis on Eμ-myc mice.
Figure 2: Eμ-myc aggravates the symptoms of the Seckel syndrome.
Figure 3: Atr suppresses Myc-induced replicative stress and apoptosis.
Figure 4: Treatment of Myc-induced lymphomas with Chk1 inhibitors.
Figure 5: Effect of Chk1 inhibitors in Myc- or Ras-driven pancreatic tumors.

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Acknowledgements

We thank M. Serrano for critical comments on the manuscript and F.X. Real for advice on the Ela-myc model. M.M. is supported a grant from Fondo de Investigaciones Sanitarias (PI080220). T.S. is supported by German Research Foundation (DFG) Research Fellowship (SCHL 1945/1-1). Work in O.F.-C.'s laboratory is supported by grants from the Spanish Ministry of Science (CSD2007-00017 and SAF2008-01596), Miguel Catalan Award from the Community of Madrid, European Molecular Biology Organization (EMBO) Young Investigator Programme and the European Research Council (ERC-210520).

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Author notes

  1. Matilde Murga and Stefano Campaner: These authors contributed equally to this work.

Authors and Affiliations

  1. Genomic Instability Group, Spanish National Cancer Research Centre, Madrid, Spain

    Matilde Murga, Andres J Lopez-Contreras, Luis I Toledo, Rebeca Soria, Maria F Montaña & Oscar Fernandez-Capetillo

  2. Department of Experimental Oncology, European Institute of Oncology, at the Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology Foundation–European Institute of Oncology Campus, Milan, Italy

    Stefano Campaner, Luana D'Artista, Thomas Schleker & Bruno Amati

  3. Experimental Oncology Group, Spanish National Cancer Research Centre, Madrid, Spain

    Carmen Guerra & Mariano Barbacid

  4. Clinical Research Program, Spanish National Cancer Research Centre, Madrid, Spain

    Elena Garcia & Manuel Hidalgo

  5. Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, at the Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology Foundation–European Institute of Oncology Campus, Milan, Italy

    Bruno Amati

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Contributions

O.F.-C. designed the study and experiments and wrote the paper. M.M. conducted most of the experiments presented. A.J.L.-C. conducted the work with the xenografts and the R26-MERT2 system. L.I.T. helped with the MycER experiments. L.D., T.S., S.C. and B.A. conducted lymphoma chemotherapy and contributed to the discussion of the manuscript. M.F.M. and R.S. analyzed Seckel MEFs, embryos and tumors. C.G. and M.B. worked on K-RasG12V-induced pancreatic tumors. E.G. and M.H. helped to design and worked with xenograft models.

Corresponding authors

Correspondence to Matilde Murga or Oscar Fernandez-Capetillo.

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The authors declare no competing financial interests.

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Murga, M., Campaner, S., Lopez-Contreras, A. et al. Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat Struct Mol Biol 18, 1331–1335 (2011). https://doi.org/10.1038/nsmb.2189

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