title: mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice.
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.
authors: Ludwig Institute for Cancer Research, Melbourne-Parkville Branch, Parkville, Victoria, Australia.
authors: Stefan
authors: S
authors: Thiem
authors: Thomas P
authors: TP
authors: Pierce
authors: Michelle
authors: M
authors: Palmieri
authors: Tracy L
authors: TL
authors: Putoczki
authors: Michael
authors: M
authors: Buchert
authors: Adele
authors: A
authors: Preaudet
authors: Ryan O
authors: RO
authors: Farid
authors: Chris
authors: C
authors: Love
authors: Bruno
authors: B
authors: Catimel
authors: Zhengdeng
authors: Z
authors: Lei
authors: Steve
authors: S
authors: Rozen
authors: Veena
authors: V
authors: Gopalakrishnan
authors: Fred
authors: F
authors: Schaper
authors: Michael
authors: M
authors: Hallek
authors: Alex
authors: A
authors: Boussioutas
authors: Patrick
authors: P
authors: Tan
authors: Andrew
authors: A
authors: Jarnicki
authors: Matthias
authors: M
authors: Ernst
mesh_terms: D000818:Animals; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D000068338:Everolimus; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
chemical_list: D018836:Inflammation Mediators; D046912:Multiprotein Complexes; D011506:Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus