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Cancer Res. 2013 Oct 1;73(19):5974-84. doi: 10.1158/0008-5472.CAN-13-1384. Epub 2013 Aug 13.

Notch1 is required for Kras-induced lung adenocarcinoma and controls tumor cell survival via p53.

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Authors' Affiliations: Department of Cancer Biology, The Scripps Research Institute, Jupiter; Molecular Oncology Program, DeWitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida; The Wistar Institute; Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine; Department of Cancer Biology, Abramson Family Cancer Research Institute; and Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and Ecole Polytechnique Fédérale de Lausanne, EPFL SV ISREC, Lausanne, Switzerland.


The Notch pathway has been implicated in a number of malignancies with different roles that are cell- and tissue-type dependent. Notch1 is a putative oncogene in non-small cell lung cancer (NSCLC) and activation of the pathway represents a negative prognostic factor. To establish the role of Notch1 in lung adenocarcinoma, we directly assessed its requirement in Kras-induced tumorigenesis in vivo using an autochthonous model of lung adenocarcinoma with concomitant expression of oncogenic Kras and deletion of Notch1. We found that Notch1 function is required for tumor initiation via suppression of p53-mediated apoptosis through the regulation of p53 stability. These findings implicate Notch1 as a critical effector in Kras-driven lung adenocarcinoma and as a regulator of p53 at a posttranslational level. Moreover, our study provides new insights to explain, at a molecular level, the correlation between Notch1 activity and poor prognosis in patients with NSCLC carrying wild-type p53. This information is critical for design and implementation of new therapeutic strategies in this cohort of patients representing 50% of NSCLC cases.

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