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

Abstract

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

Green tea polyphenol EGCG suppresses cigarette smoke condensate-induced NF-κB activation in normal human bronchial epithelial cells

“…mTOR, a serine/threonine kinase downstream of AKT, plays a vital role in the control of cell growth and proliferation through integration of mitogenic signals and intracellular nutrient levels. mTOR signaling has been shown to be activated in precursors of lung adenocarcinoma with a role in lung tumor progression (Wislez et al, 2005). Our data show that EGCG may have a potential chemopreventive role by blocking PI3K/AKT/MTOR signaling pathway, a critical target in the proliferation and malignant transformation of normal cells (Figure 6).…”

Rapamycin for Chemoprevention of Upper Aerodigestive Tract Cancers

“…It is also unclear from these studies whether rapamycin exerted antitumor effects through direct inhibition of other cell types such as endothelial cells or lymphocytes. Such tumor cell autonomous effects might be important because Wislez et al (14) previously showed that modulation of chemokine signaling and macrophage function was important for inhibition of K-Ras-driven lung tumorigenesis by a rapamycin analogue.…”

The role of mTORC1 pathway in intestinal tumorigenesis

“…8 Essential roles of the mTORC1 activation in tumorigenesis induced by these upstream mutations are supported by studies using mouse models. Namely, mTORC1 activation has been observed in tumors that developed in transgenic mice carrying constitutively active allele of Akt or K-ras, [9][10][11][12] in Pten knockout mice, 13,14 and in mice with prostate-specific Rheboverexpression. 15 Importantly, tumors in these mice were all sensitive to treatment with rapamycin or its derivatives (except Rheb transgenic mice that were not tested).…”