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Title: mTORC1 inhibition restricts infammation-associated gastrointestinal tumorigenesis in mice
Authors: Thiem, S.
Pierce, T.P.
Palmieri, M.
Putoczki, T.L.
Buchert, M.
Preaudet, A.
Farid, R.O.
Love, C.
Catimel, B.
Lei, Z.
Rozen, S. 
Gopalakrishnan, V.
Schaper, F.
Hallek, M.
Boussioutas, A.
Tan, P. 
Jarnicki, A.
Ernst, M.
Issue Date: 1-Feb-2013
Citation: Thiem, S., Pierce, T.P., Palmieri, M., Putoczki, T.L., Buchert, M., Preaudet, A., Farid, R.O., Love, C., Catimel, B., Lei, Z., Rozen, S., Gopalakrishnan, V., Schaper, F., Hallek, M., Boussioutas, A., Tan, P., Jarnicki, A., Ernst, M. (2013-02-01). mTORC1 inhibition restricts infammation-associated gastrointestinal tumorigenesis in mice. Journal of Clinical Investigation 123 (2) : 767-781. ScholarBank@NUS Repository.
Abstract: 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.
Source Title: Journal of Clinical Investigation
ISSN: 00219738
DOI: 10.1172/JCI65086
Appears in Collections:Staff Publications

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