Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma (original) (raw)

Nature volume 462, pages 104–107 (2009)Cite this article

Abstract

NF-κB transcription factors function as crucial regulators of inflammatory and immune responses as well as of cell survival1. They have also been implicated in cellular transformation and tumorigenesis2,3,4,5,6. However, despite extensive biochemical characterization of NF-κB signalling during the past twenty years, the requirement for NF-κB in tumour development in vivo, particularly in solid tumours, is not completely understood. Here we show that the NF-κB pathway is required for the development of tumours in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (also known as Trp53) and expression of oncogenic Kras(G12D) resulted in NF-κB activation in primary mouse embryonic fibroblasts. Conversely, in lung tumour cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-κB inhibition. Furthermore, the inhibition of NF-κB signalling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumours in vivo, from the time of tumour initiation or after tumour progression, resulted in significantly reduced tumour development. Together, these results indicate a critical function for NF-κB signalling in lung tumour development and, further, that this requirement depends on p53 status. These findings also provide support for the development of NF-κB inhibitory drugs as targeted therapies for the treatment of patients with defined mutations in Kras and p53.

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Acknowledgements

We thank D. McFadden, T. Oliver, M. DuPage, K. Lane, A. Cheung, M. Kumar and E. Snyder for discussions and for sharing various reagents, A. Deconinck for critical reading of the manuscript, D. Crowley for preparation of tissue sections, and the entire Jacks laboratory for discussions. This work was supported by the Howard Hughes Medical Institute (T.J.) and partially by a Cancer Center Support grant from the NCI (P30-CA14051). T.J. is the David H. Koch Professor of Biology and a Daniel K. Ludwig Scholar. E.M. is a recipient of fellowships from the International Human Frontier Science Program Organization and the Swiss National Science Foundation. D.M.F. is a recipient of a Leukemia & Lymphoma Society Fellow Award.

Author Contributions E.M. and T.J. designed the study; E.M., A.L.D., L.S. and E.T. performed the experiments; D.M.F. generated the mouse lung cancer model with restorable p53; C.O. generated lung cell lines from tumours of these mice; E.M. and T.J. analysed the data; E.M. wrote the paper; and A.L.D. and T.J. edited the paper.

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Authors and Affiliations

  1. and Department of Biology, Koch Institute for Integrative Cancer Research, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA,
    Etienne Meylan, Alison L. Dooley, David M. Feldser, Lynn Shen, Erin Turk, Chensi Ouyang & Tyler Jacks

Authors

  1. Etienne Meylan
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  2. Alison L. Dooley
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  3. David M. Feldser
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  4. Lynn Shen
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  5. Erin Turk
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  6. Chensi Ouyang
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  7. Tyler Jacks
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Corresponding author

Correspondence toTyler Jacks.

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Meylan, E., Dooley, A., Feldser, D. et al. Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma.Nature 462, 104–107 (2009). https://doi.org/10.1038/nature08462

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Editorial Summary

Targeting KRAS cancers

Mutations in genes of the RAS family are preset on about 20% of human cancers, making RAS proteins prime potential targets for cancer therapy. Direct targeting of RAS proteins has not so far been productive, but two papers published in this issue offer the prospect of alternative targets in a signalling pathway downstream of RAS. Using a synthetic lethality RNAi screen, Barbie et al. identify TBK1 as a kinase in the NF-κB signalling pathway that is essential for the survival of _KRAS_-transformed cells. TBK1 induces anti-apoptotic signals and may be a therapeutic cancer target. And in an elegant mouse model for lung cancer driven by Kras mutation and loss of p53, Meylan et al. show that NF-κB signalling is activated by the concerted actions of these two alterations and required for tumour initiation and tumour maintenance.

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