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, Gregory B. Lesinski

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)44509-44522
Number of pages14
JournalOncotarget
Volume6
Issue number42
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

Pancreatic Neoplasms
Adenocarcinoma
Pancreas
Phosphorylation
Cell Line
Survival
N,N-dicyclopropyl-4-((1,5-dimethyl-1H-pyrazol-3-yl)amino)-6-ethyl-1-methyl-1,6-dihydroimidazo(4,5-d)pyrrolo(2,3b)pyridine-7-carboxamide
Regulatory T-Lymphocytes
Tumor Burden
Alleles
In Vitro Techniques
Neoplasms

Keywords

  • Jak2
  • Pancreatic cancer
  • STAT3
  • STAT5

ASJC Scopus subject areas

  • Oncology

Cite this

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

In: Oncotarget, Vol. 6, No. 42, 01.01.2015, p. 44509-44522.

Research output: Contribution to journalArticle

Mace, TA, Shakya, R, Elnaggar, O, Wilson, K, Komar, HM, Yang, J, Pitarresi, JR, Young, GS, Ostrowski, MC, Ludwig, T, Bekaii-Saab, T, Bloomston, M & Lesinski, GB 2015, 'Single agent BMS-911543 Jak2 inhibitor has distinct inhibitory effects on STAT5 signaling in genetically engineered mice with pancreatic cancer', Oncotarget, vol. 6, no. 42, pp. 44509-44522. https://doi.org/10.18632/oncotarget.6332
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. / Single agent BMS-911543 Jak2 inhibitor has distinct inhibitory effects on STAT5 signaling in genetically engineered mice with pancreatic cancer. In: Oncotarget. 2015 ; Vol. 6, No. 42. pp. 44509-44522.
@article{8104ccabe4db4cfaa624ac200a308ac4,
title = "Single agent BMS-911543 Jak2 inhibitor has distinct inhibitory effects on STAT5 signaling in genetically engineered mice with pancreatic cancer",
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.",
keywords = "Jak2, Pancreatic cancer, STAT3, STAT5",
author = "Mace, {Thomas A.} and Reena Shakya and Omar Elnaggar and Kristin Wilson and Komar, {Hannah M.} and Jennifer Yang and Pitarresi, {Jason R.} and Young, {Gregory S.} and Ostrowski, {Michael C.} and Thomas Ludwig and Tanios Bekaii-Saab and Mark Bloomston and Lesinski, {Gregory B.}",
year = "2015",
month = "1",
day = "1",
doi = "10.18632/oncotarget.6332",
language = "English (US)",
volume = "6",
pages = "44509--44522",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "42",

}

TY - JOUR

T1 - Single agent BMS-911543 Jak2 inhibitor has distinct inhibitory effects on STAT5 signaling in genetically engineered mice with pancreatic cancer

AU - Mace, Thomas A.

AU - Shakya, Reena

AU - Elnaggar, Omar

AU - Wilson, Kristin

AU - Komar, Hannah M.

AU - Yang, Jennifer

AU - Pitarresi, Jason R.

AU - Young, Gregory S.

AU - Ostrowski, Michael C.

AU - Ludwig, Thomas

AU - Bekaii-Saab, Tanios

AU - Bloomston, Mark

AU - Lesinski, Gregory B.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - 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.

AB - 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.

KW - Jak2

KW - Pancreatic cancer

KW - STAT3

KW - STAT5

UR - http://www.scopus.com/inward/record.url?scp=84953455763&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84953455763&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.6332

DO - 10.18632/oncotarget.6332

M3 - Article

C2 - 26575024

AN - SCOPUS:84953455763

VL - 6

SP - 44509

EP - 44522

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 42

ER -