Therapeutic inhibition of Jak activity inhibits progression of gastrointestinal tumors in mice
- Author(s)
- Stuart, EC; Buchert, M; Putoczki, T; Thiem, S; Farid, R; Elzer, J; Huszar, D; Waring, PM; Phesse, TJ; Ernst, M;
- Details
- Publication Year 2014-01-07,Volume 13,Issue #2,Page 468-74
- Journal Title
- Molecular cancer therapeutics
- Publication Type
- Journal Article
- Abstract
- Aberrant activation of the latent transcription factor STAT3 and its downstream targets is a common feature of epithelial-derived human cancers, including those of the gastrointestinal tract. Mouse models of gastrointestinal malignancy implicate Stat3 as a key mediator of inflammatory driven-tumorigenesis, where its cytokine/gp130/Jak-dependent activation provides a functional link through which the microenvironment sustains tumor promotion. Although therapeutic targeting of STAT3 is highly desirable, such molecules are not available for immediate clinical assessment. Here we investigated whether the small molecule Jak1/2 inhibitor AZD1480 confers therapeutic benefits in two mouse models of inflammation-associated gastrointestinal cancer, which are strictly dependent of excessive Stat3 activation. We confirm genetically that Cre-mediated, tumor cell-specific reduction of Stat3 expression arrests the growth of intestinal-type gastric tumors in gp130F/F mice. We find that systemic administration of AZD1480 readily replicates this effect, which is associated with reduced Stat3 activation and correlates with diminished tumor cell proliferation and increased apoptosis. Likewise, AZD1480 therapy also conferred a cytostatic effect on established tumors in a colitis-associated colon cancer model in wild-type mice. As predicted from our genetic observations in gp130F/F mice, the therapeutic effect of AZD1480 remains fully reversible upon cessation of compound administration. Collectively, our results provide the first evidence that pharmacological targeting of excessively activated wild-type Jak kinases affords therapeutic suppression of inflammation-associated gastrointestinal cancers progression in vivo.
- Publisher
- AACR
- Keywords
- Jak/Stat3, gastrointestinal cancer, inflammation-associated cancer
- Research Division(s)
- Inflammation; Cell Signalling And Cell Death
- Publisher's Version
- https://doi.org/10.1158/1535-7163.MCT-13-0583-T
- Terms of Use/Rights Notice
- © 2014 American Association for Cancer Research.
Creation Date: 2014-01-20 02:17:03