Author/Authors :
Maraver، نويسنده , , Antonio and Fernandez-Marcos، نويسنده , , Pablo J. and Herranz، نويسنده , , Daniel and Caٌamero، نويسنده , , Marta and Muٌoz-Martin، نويسنده , , Maribel and Gَmez-Lَpez، نويسنده , , Gonzalo and Mulero، نويسنده , , Francisca and Megيas، نويسنده , , Diego and Sanchez-Carbayo، نويسنده , , Marta and Shen، نويسنده , , Jie and Sanchez-Cespedes، نويسنده , , Montserrat and Palomero، نويسنده , , Teresa and Ferrando، نويسنده , , Adolfo and Serrano، نويسنده , , Manuel، نويسنده ,
Abstract :
Summary
we have investigated the role of the Notch pathway in the generation and maintenance of KrasG12V-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.
