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Mol Cancer Ther. 2019 Sep 23. pii: molcanther.0508.2019. doi: 10.1158/1535-7163.MCT-19-0508. [Epub ahead of print]

Enzalutamide Induced Feed-Forward Signaling Loop Promotes Therapy-Resistant Prostate Cancer Growth Providing an Exploitable Molecular Target for Jak2 Inhibitors.

Author information

1
Department of Pathology, Department of Pharmacology & Toxicology, Prostate Cancer Center of Excellence at Medical College of Wisconsin Cancer Center, Medical College of Wisconsin.
2
Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University.
3
Insitiute for Molecular Medicine Finland and Medicum, University of Helsinki.
4
Biostatistics, Medical College of Wisconsin.
5
Pathology, Medical College of Wisconsin.
6
Urologic Surgery, Medical College of Wisconsin.
7
Division of Urology, Froedtert Memorial Lutheran Hospital.
8
Department of Pathology, Haartman Institute, University of Helsinki.
9
Prostate Cancer Center of Excellence at Medical College of Wisconsin Cancer Center, Medical College of Wisconsin.
10
Department of Pathology, Department of Pharmacology & Toxicology, Prostate Cancer Center of Excellence at Medical College of Wisconsin Cancer Center, Medical College of Wisconsin mnevalainen@mcw.edu.

Abstract

The second-generation anti-androgen, enzalutamide (ENZ), is approved for castrate-resistant (CR) PC and targets androgen receptor (AR) activity in CRPC. Despite initial clinical activity, acquired resistance to ENZ arises rapidly and most patients develop terminal disease. Previous work has established Stat5 as a potent inducer of PC growth. Here, we investigated the significance of Jak2-Stat5 signaling in resistance of PC to ENZ. The levels of Jak2 and Stat5 mRNA, proteins and activation were evaluated in PC cells, xenograft tumors and clinical PCs before and after ENZ therapy. Jak2 and Stat5 were suppressed by genetic knockdown using lentiviral shRNA or pharmacological inhibitors. Responsiveness of primary and ENZ resistant PC to pharmacological inhibitors of Jak2-Stat5 signaling was assessed in vivo in mice bearing PC xenograft tumors. Patient-derived PCs were tested for responsiveness to Stat5 blockade as second line treatment after ENZ ex vivo in tumor explant cultures. ENZ-liganded AR induces sustained Jak2-Stat5 phosphorylation in PC leading to a formation of a positive feed-forward loop, where activated Stat5, in turn, induces Jak2 mRNA and protein levels contributing to further Jak2 activation. Mechanistically, ENZ-liganded AR induced Jak2 phosphorylation through a process involving Jak2-specific phosphatases. Stat5 promoted PC growth during ENZ treatment. Jak2-Stat5 inhibition induced death of PC cells and patient-derived PCs surviving ENZ treatment and blocked ENZ-resistant tumor growth in mice. This work introduces a novel concept of a pivotal role of hyperactivated Jak2-Stat5 signaling in ENZ-resistant PC which is readily targetable by Jak2 inhibitors in clinical development.

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