Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-α catalytic subunit ( PIK3CA ) 1 . They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the PIK3CA mutants are transforming in vitro , their oncogenic potential has not been assessed in genetically engineered mouse models. Furthermore, clinical trials with PI3K inhibitors have recently been initiated, and it is unknown if their efficacy will be restricted to specific, genetically defined malignancies. In this study, we engineered an inducible bitransgenic mouse model that develops lung adenocarcinomas initiated and maintained by expression of p110-α H1047R. Treatment of these tumors with NVP-BEZ235, a dual pan PI3K/mTOR inhibitor in clinical development, led to marked tumor regression as shown by PET-CT, MRI and microscopic examination. In contrast, mouse lung cancers driven by mutant K-Ras did not substantially respond to single-agent NVP-BEZ235. However, when NVP-BEZ235 was combined with a MEK inhibitor, ARRY-142886, there was dramatic synergy in shrinking these K-Ras mutant cancers. These in vivo studies suggest that inhibitors of the PI3K/mTOR pathway may be active in cancers with PIK3CA mutations, and, when combined with MEK inhibitors, may effectively treat K-RAS mutated lung cancers.