mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice

作者：Thiem Stefan; Pierce Thomas P; Palmieri Michelle; Putoczki Tracy L; Buchert Michael; Preaudet Adele; Farid Ryan O; Love Chris; Catimel Bruno; Lei Zhengdeng; Rozen Steve; Gopalakrishnan Veena; Schaper Fred; Hallek Michael; Boussioutas Alex; Tan Patrick; Jarnicki Andrew; Ernst Matthias^*

来源：Journal of Clinical Investigation, 2013, 123(2): 767-781.

DOI：10.1172/JCI65086

Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs). Furthermore, in a preclinical mouse model of IGC, GP130 ligand administration simultaneously activated mTORC1/S6 kinase and STAT3 signaling. We therefore investigated whether mTORC1 activation was required for inflammation-associated gastrointestinal tumorigenesis. Strikingly, the mTORC1-specific inhibitor RAD001 potently suppressed initiation and progression of both murine IGC and colitis-associated colon cancer. The therapeutic effect of RAD001 was associated with reduced tumor vascularization and cell proliferation but occurred independently of STAT3 activity. We analyzed the mechanism of GP130-mediated mTORC1 activation in cells and mice and revealed a requirement for JAK and PI3K activity but not for GP130 tyrosine phosphorylation or STAT3. Our results suggest that GP130-dependent activation of the druggable PI3K/mTORC1 pathway is required for inflammation-associated gastrointestinal tumorigenesis. These findings advocate clinical application of PI3K/mTORC1 inhibitors for the treatment of corresponding human malignancies.

• 出版日期2013-2
• 单位河北医科大学