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

• Published in: Oncotarget 2015-12, Vol.6 (42), p.44509-44522
• Main Authors: Mace, Thomas A, Shakya, Reena, Elnaggar, Omar, Wilson, Kristin, Komar, Hannah M, Yang, Jennifer, Pitarresi, Jason R, Young, Gregory S, Ostrowski, Michael C, Ludwig, Thomas, Bekaii-Saab, Tanios, Bloomston, Mark, Lesinski, Gregory B
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - enzymology; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - pathology; Cell Survival - drug effects; Disease Models, Animal; Dose-Response Relationship, Drug; Forkhead Transcription Factors - metabolism; Genes, BRCA1; Genes, p53; Genes, ras; Genetic Predisposition to Disease; Heterocyclic Compounds, 3-Ring - pharmacology; Janus Kinase 2 - antagonists & inhibitors; Janus Kinase 2 - metabolism; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphocytes, Tumor-Infiltrating - pathology; Mice, Transgenic; Molecular Targeted Therapy; Mutation; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - enzymology; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Phenotype; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Research Paper; Signal Transduction - drug effects; STAT5 Transcription Factor - metabolism; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - pathology; Time Factors; Tumor Burden
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.6332

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.