Inhibition of Mammalian Target of Rapamycin Reverses Alveolar Epithelial Neoplasia Induced by Oncogenic K-ras

摘要: The serine/threonine kinase AKT and its downstream mediator mammalian target of rapamycin (mTOR) are activated in lung adenocarcinoma, clinical trials under way to test whether inhibition mTOR is useful treating cancer. Here, we report that blocked malignant progression K-ras(LA1) mice, which undergo somatic activation the K-ras oncogene display morphologic changes alveolar epithelial cells recapitulate those precursors human adenocarcinoma. Levels phospho-S6(Ser236/235), a mTOR, increased with (normal adenocarcinoma) mice patients Atypical hyperplasia, an early neoplastic change, was prominently associated macrophages expressed high levels phospho-S6(Ser236/235). by treatment analogue CCI-779 reduced size number lesions (atypical hyperplasia adenomas) induced apoptosis intraepithelial macrophages. LKR-13, adenocarcinoma cell line derived from resistant vitro. However, LKR-13 grown as syngeneic tumors recruited macrophages, regressed response CCI-779. Lastly, conditioned medium primary cultures stimulated proliferation cells. These findings provide evidence expansion oncogenic requires mTOR-dependent signaling host factors play critical role progression.