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, in which its cytokine/gp130/Janus kinase (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 gp130(F/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 gp130(F/F) mice, the therapeutic effect of AZD1480 remains fully reversible upon cessation of compound administration. Collectively, our results provide the first evidence that pharmacologic targeting of excessively activated wild-type Jak kinases affords therapeutic suppression of inflammation-associated gastrointestinal cancers progression in vivo.
Highlights
Aberrant activation of the latent transcription factor STAT3 is a common molecular characteristic of many epithelial-derived human cancers [1]
STAT3 activation is observed in response to various growth factors and cytokines, the interleukin (IL)6 family of cytokines, defined by their shared use of the GP130 receptor b-chain, arguably play the most important role during tumor promotion [3]
Systemic reduction of Stat3 expression in gp130F/F;Stat3þ/À mice delays the onset and reduces the growth of tumors [8], it remains unclear whether this is directly attributable to excessive Stat3 activity in the metaplastic epithelium of tumors gp130F/F mice
Summary
Aberrant activation of the latent transcription factor STAT3 is a common molecular characteristic of many epithelial-derived human cancers [1]. STAT3 plays a critical role in controlling transcriptional programs that fuel many processes necessary for tumor promotion [2]. STAT3 activation is observed in response to various growth factors and cytokines, the interleukin (IL) family of cytokines, defined by their shared use of the GP130 receptor b-chain, arguably play the most important role during tumor promotion [3]. Authors' Affiliations: 1The Walter and Eliza Hall Institute of Medical Research; 2Department of Pathology, The University of Melbourne, Parkville; 3Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia; and 4AstraZeneca, Oncology iMed, Waltham, Massachusetts. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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