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p53 loss does not permit escape from BrafV600E-induced senescence in a mouse model of lung cancer

Oncogene volume 36, pages 6325–6335 (2017)Cite this article

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Abstract

Lung cancer arises through the acquisition of a number of genetic lesions, with a preponderance of activating mutations in the canonical mitogen-activated protein kinase (MAPK) cascade (RTK-RAS-RAF-MEK). BrafV600E expression induces benign lung adenomas that fail to progress to adenocarcinoma because of oncogene-induced senescence (OIS). BrafV600E expression, coupled with simultaneous p53 ablation, permits bypass of senescence and progression to lung adenocarcinoma. However, spontaneous human tumors sustain mutations in a temporally separated manner. Here, we use a mouse lung cancer model where oncogene activation (BrafV600E expression) and tumor suppressor loss (p53 ablation) are independently controlled through the actions of Flp and Cre recombinase, respectively. We show that p53 loss before OIS is permissive for the transition from lung adenoma to adenocarcinoma. In contrast, p53 loss after senescence is established fails to enable escape from senescence and disease progression. This study demonstrates that BrafV600E induced senescence is irreversible in vivo and suggests that therapy-induced senescence would halt further tumor progression.

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Acknowledgements

DD would like to thank Martin McMahon for his generosity and guidance, which enabled this work. We thank members of the Dankort lab for discussions, Eve Bigras for administrative assistance, Drs Siegfried Hekimi, Alain Nepveu and Peter M Siegel for critical comments. We thank the lab of Dr Hoang Trang for providing necessary reagents. These studies were supported by grants from the Canadian Institutes of Health Research (CIHR, MOP-97925), Canadian Cancer Society Research Initiative (no. 704228) and Cancer Research Society (no. 19087).

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  1. Department of Biology, McGill University, Montréal, QC, Canada

    S Garnett, K L Dutchak, R V McDonough & D Dankort

  2. Goodman Cancer Research Centre, Montréal, QC, Canada

    D Dankort

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Garnett, S., Dutchak, K., McDonough, R. et al. p53 loss does not permit escape from BrafV600E-induced senescence in a mouse model of lung cancer. Oncogene 36, 6325–6335 (2017). https://doi.org/10.1038/onc.2017.235

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