| Literature DB >> 22897852 |
Pablo J Fernández-Marcos1, Daniel Herranz1,2, Antonio Maraver1, Maribel Muñoz-Martin1, Gonzalo Gomez-Lopez3, Marta Cañamero4, Francisca Mulero5, Diego Megías6, Marta Sanchez-Carbayo7, Jie Shen8, Montserrat Sanchez-Cespedes9, Teresa Palomero2, Adolfo Ferrando2, Manuel Serrano1.
Abstract
Here, we have investigated the role of the Notch pathway in the generation and maintenance of Kras(G12V)-driven non-small cell lung carcinomas (NSCLCs). We demonstrate by genetic means that γ-secretase and RBPJ are essential for the formation of NSCLCs. Of importance, pharmacologic treatment of mice carrying autochthonous NSCLCs with a γ-secretase inhibitor (GSI) blocks cancer growth. Treated carcinomas present reduced HES1 levels and reduced phosphorylated ERK without changes in phosphorylated MEK. Mechanistically, we show that HES1 directly binds to and represses the promoter of DUSP1, encoding a dual phosphatase that is active against phospho-ERK. Accordingly, GSI treatment upregulates DUSP1 and decreases phospho-ERK. These data provide proof of the in vivo therapeutic potential of GSIs in primary NSCLCs.Entities:
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Year: 2012 PMID： 22897852 PMCID： PMC3813920 DOI： 10.1016/j.ccr.2012.06.014
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743