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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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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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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