Blockade Of The Il-6/Jak/Stat3 Signaling Pathway Inhibits Pancreatic Tumor Cell Growth In 3d Spheroid Cultures And In Xenograft Models

Emerging evidence has demonstrated the importance of tumor-associated inflammation in the development and progression of pancreatic ductal adenocarcinoma. Specifically, constitutive activation of the inflammation-related IL-6/JAK/STAT3 signaling pathway has been reported in pancreatic tumors and has been suggested to be a poor prognostic factor for overall survival in patients with advanced disease. The aim of this study was to assess the effects of inhibition of IL-6/JAK/STAT3 signaling on pancreatic cell growth in vitro and tumor growth in vivo. INCB039110, a JAK1 selective inhibitor currently in multiple Phase 2 clinical trials, was used to block the IL-6/JAK/STAT3 signaling pathway in cells. We show that while inhibition of IL-6/JAK/STAT3 signaling by INCB039110 showed no effects on the proliferation of pancreatic cell lines grown under conventional 2D monolayer cell culture conditions, this inhibitor demonstrated growth inhibitory activity against the pancreatic tumor cell lines, Hs700T and BxPC-3, in a 3D-spheroid culture system. Importantly, addition of cytokines that stimulated JAK/STAT3 signaling in these cells significantly promoted the growth of the spheroids, and this could be completely reversed by INCB039110. Furthermore, JAK1 inhibition enhanced the cytotoxicity induced by gemcitabine in both Hs700T and BxPC-3 spheroids in a combination study. The results were confirmed with another novel Jak1 selective inhibitor, INCB052793 which is currently in a Phase 1 clinical trial in patients with advanced malignancies. Since elevated serum IL-6 and its correlation with cachexia has been observed in pancreatic cancer, we tested and found that INCB039110 prevented weight loss in an IL-6 induced cachexia model in mice. Finally, we show that INCB039110 blocked tumor growth in human pancreatic xenograft models in mice at clinically relevant doses, both as monotherapy and in combination with cytotoxic agents such as gemcitabine. Thus, we demonstrate that pharmacological blockade of the IL-6/JAK/STAT3 signaling pathway with a JAK1 selective inhibitor can have both tumor intrinsic and extrinsic effects resulting in the inhibition of pancreatic tumor cell growth and the modulation of inflammation-associated cachexia. These data suggest that pancreatic cancer patients may potentially benefit from JAK1 inhibitors in the clinic. Citation Format: Jun Li, Eian Caulder, Margaret Favata, Melody Diamond, Beth Rumberger, Holly Koblish, Taisheng Huang, Chu-Biao Xue, Wenqing Yao, Jordan Fridman, Peggy Scherle, Mike Liu, Reid Huber, Kris Vaddi. Blockade of the IL-6/JAK/STAT3 signaling pathway inhibits pancreatic tumor cell growth in 3D spheroid cultures and in xenograft models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 779. doi:10.1158/1538-7445.AM2015-779