Therapeutic Effect of γ-Secretase Inhibition in KrasG12V-Driven Non-Small Cell Lung Carcinoma by Derepression of DUSP1 and Inhibition of ERK

SummaryHere, 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (215 K)Download as PowerPoint slideHighlights► The canonical Notch pathway is needed for KrasG12V-driven NSCLCs formation ► Pharmacological inhibition of γ-secretase in vivo arrests primary NSCLCs ► Inhibition of γ-secretase induces phosphatase DUSP1 and reduces ERK phosphorylation ► The Notch effector HES1 binds to the DUSP1 promoter and inhibits its expression