Here, 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 in the formation of NSCLCs. Importantly, pharmacologic treatment of mice carrying autochthonous NSCLCs with a γ-secretase inhibitor (GSI) blocks cancer growth. Treated carcinomas present reduced HES1 levels and, interestingly, reduced phosphorylated ERK without changes in phosphorylated MEK. Mechanistically, we show that HES1 directly binds and represses the promoter of DUSP1, encoding a dual phosphatase active against phospho-ERK. Accordingly, GSI treatment upregulates DUSP1 and decreases phospho-ERK. These data provide proof for the in vivo therapeutic potential of γ-secretase inhibitors in primary NSCLCs.