Selective activation of p53-mediated tumour suppression in high-grade tumours (original) (raw)

Nature volume 468, pages 567–571 (2010)Cite this article

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Abstract

Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide, with an overall 5-year survival rate of only 10–15%1. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras2. p53 is also frequently inactivated in NSCLC and, because oncogenic Ras can be a potent trigger of p53 (ref. 3), it seems likely that oncogenic Ras signalling has a major and persistent role in driving the selection against p53. Hence, pharmacological restoration of p53 is an appealing therapeutic strategy for treating this disease4. Here we model the probable therapeutic impact of p53 restoration in a spontaneously evolving mouse model of NSCLC initiated by sporadic oncogenic activation of endogenous Kras5. Surprisingly, p53 restoration failed to induce significant regression of established tumours, although it did result in a significant decrease in the relative proportion of high-grade tumours. This is due to selective activation of p53 only in the more aggressive tumour cells within each tumour. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signalling sensor p19 ARF(ref. 6). Our data indicate that p53-mediated tumour suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumour evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers.

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Acknowledgements

We are indebted to T. Jacks for the KR mice, C. Sherr and M. Roussel for the p19 ARF antibody, M. Dail and A.-T. Maia for advice on Kras copy number analysis and V. Weinberg for guidance on statistical analysis. We also thank D. Tuveson and all the members of the Evan laboratory for their comments. This work was supported by grants NCI CA98018, NCI CA100193, AICR 09-0649, the Ellison Medical Foundation and from the Samuel R. Waxman Cancer Research Foundation (all to G.I.E.). M.R.J. is the Enrique Cepero, PhD Fellow of the Damon Runyon Cancer Research Foundation.

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  1. Melissa R. Junttila, Gerard I. Evan & Carla P. Martins
    Present address: Present addresses: Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK (C.P.M.); Department of Biochemistry, Tennis Court Road, University of Cambridge, Cambridge CB2 1GA, UK (G.I.E.); Department of Molecular Biology, Genentech. Inc. South San Francisco, CA 94080 , USA (M.R.J.).,

Authors and Affiliations

  1. Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, 94143-0502, California, USA
    Melissa R. Junttila, Anthony N. Karnezis, Daniel Garcia, Roderik M. Kortlever, Fanya Rostker, Lamorna Brown Swigart, Gerard I. Evan & Carla P. Martins
  2. Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK
    Francesc Madriles
  3. Department of Radiology and Biomedical Imaging and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, 94143, California, USA
    David M. Pham & Youngho Seo

Authors

  1. Melissa R. Junttila
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  2. Anthony N. Karnezis
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  3. Daniel Garcia
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  4. Francesc Madriles
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  5. Roderik M. Kortlever
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  6. Fanya Rostker
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  7. Lamorna Brown Swigart
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  8. David M. Pham
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  9. Youngho Seo
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  10. Gerard I. Evan
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  11. Carla P. Martins
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Contributions

C.P.M. and G.I.E. designed this study with help from M.R.J. C.P.M. and M.R.J. performed all experiments with assistance from D.G. and F.M. C.P.M., M.R.J. and G.I.E. analysed and interpreted the data. A.N.K. graded all tumours. L.B.S., F.R. and R.M.K. helped maintain the mouse colony. D.M.P. and Y.S. performed the micro-computed tomography analysis. C.P.M. and G.I.E. wrote the paper with help from M.R.J. and all authors contributed to editing.

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Correspondence toGerard I. Evan.

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The authors declare no competing financial interests.

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Junttila, M., Karnezis, A., Garcia, D. et al. Selective activation of p53-mediated tumour suppression in high-grade tumours.Nature 468, 567–571 (2010). https://doi.org/10.1038/nature09526

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Editorial Summary

Limits to antitumour effect of p53 restoration

Inactivation of the p53 tumour-suppressor pathway is a common feature of human cancers, prompting suggestions that restoring p53 function in established tumours might be an effective therapy. However, two papers in this week's Nature highlight a practical limitation of p53-directed cancer therapeutics. They show in a K-Ras-driven lung-cancer model that p53-mediated tumour suppression is engaged only at a late stage of tumour progression, when the K-Ras oncogenic signal reaches a threshold that is sufficient to activate the ARF-p53 pathway. This means that p53 re-expression fails to restrict the early stages of tumorigenesis, although it does induce regression of more aggressive tumours.

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