Oncotarget

Research Papers:

Single agent BMS-911543 Jak2 inhibitor has distinct inhibitory effects on STAT5 signaling in genetically engineered mice with pancreatic cancer

Thomas A. Mace, Reena Shakya, Omar Elnaggar, Kristin Wilson, Hannah M. Komar, Jennifer Yang, Jason R. Pitarresi, Gregory S. Young, Michael C. Ostrowski, Thomas Ludwig, Tanios Bekaii-Saab, Mark Bloomston and Gregory B. Lesinski _

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Oncotarget. 2015; 6:44509-44522. https://doi.org/10.18632/oncotarget.6332

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Abstract

Thomas A. Mace1, Reena Shakya2, Omar Elnaggar1, Kristin Wilson3, Hannah M. Komar1, Jennifer Yang1, Jason R. Pitarresi4, Gregory S. Young5, Michael C. Ostrowski4, Thomas Ludwig4, Tanios Bekaii-Saab1, Mark Bloomston6, Gregory B. Lesinski1

1Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA

2Comprehensive Cancer Center, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA

3Veterinary Biosciences, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA

4Department of Molecular and Cellular Biochemistry, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA

5Center for Biostatistics, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA

6Division of Surgical Oncology, Department of Surgery, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University, Columbus, OH 43210, USA

Correspondence to:

Gregory B. Lesinski, e-mail: Gregory.Lesinski@osumc.edu

Keywords: Jak2, STAT3, STAT5, pancreatic cancer

Received: May 19, 2015     Accepted: October 22, 2015     Published: October 31, 2015

ABSTRACT

The Jak/STAT pathway is activated in human pancreatic ductal adenocarcinoma (PDAC) and cooperates with mutant Kras to drive initiation and progression of PDAC in murine models. We hypothesized that the small-molecule Jak2 inhibitor (BMS-911543) would elicit anti-tumor activity against PDAC and decrease immune suppressive features of the disease. We used an aggressive genetically engineered PDAC model with mutant KrasG12D, tp53R270H, and Brca1 alleles (KPC-Brca1 mice). Mice with confirmed tumor burden were treated orally with vehicle or 30 mg/kg BMS-911543 daily for 14 days. Histologic analysis of pancreata from treated mice revealed fewer foci of adenocarcinoma and significantly decreased Ki67+ cells versus controls. In vivo administration of BMS-911543 significantly reduced pSTAT5 and FoxP3 positive cells within the pancreas, but did not alter STAT3 phosphorylation. Continuous dosing of KPC-Brca1 mice with BMS-911543 resulted in a median survival of 108 days, as compared to a median survival of 87 days in vehicle treated animals, a 23% increase (p = 0.055). In vitro experiments demonstrated that PDAC cell lines were poorly sensitive to BMS-911543, requiring high micromolar concentrations to achieve targeted inhibition of Jak/STAT signaling. Similarly, BMS-911543 had little in vitro effect on the viability of both murine and human PDAC-derived stellate cell lines. However, BMS-911543 potently inhibited phosphorylation of pSTAT3 and pSTAT5 at low micromolar doses in human PBMC and reduced in vitro differentiation of Foxp3+ T regulatory cells. These results indicate that single agent Jak2i deserves further study in preclinical models of PDAC and has distinct inhibitory effects on STAT5 mediated signaling.


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