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

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

  • Mol Cancer Ther. 2020 Jan;19(1):231-246. doi: 10.1158/1535-7163.MCT-19-0508.
Vindhya Udhane  # 1 2 3,  Cristina Maranto  # 1 2 3,  David T Hoang 4,  Lei Gu 4,  Andrew Erickson 5 6,  Savita Devi 1 2 3,  Pooja G Talati 4,  Anjishnu Banerjee 3 7,  Kenneth A Iczkowski 1 3,  Kenneth Jacobsohn 3 8,  William A See 3 8,  Tuomas Mirtti 5 6 9,  Deepak Kilari 3 10,  Marja T Nevalainen 11 2 3
Affiliations

Affiliations

  • 1 Department of Pathology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
  • 2 Department of Pharmacology and Toxicology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
  • 3 Prostate Cancer Center of Excellence at Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
  • 4 Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • 5 Department of Pathology, Medicum, University of Helsinki, Helsinki, Finland.
  • 6 Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
  • 7 Institute for Health and Equity, Medical College of Wisconsin, Milwaukee, Wisconsin.
  • 8 Department of Urology and Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
  • 9 Department of Pathology, HUSLAB and Helsinki University Hospital, Helsinki, Finland.
  • 10 Department of Medicine, Medical College of Wisconsin and Milwaukee VA Medical Center, Milwaukee, Wisconsin.
  • 11 Department of Pathology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin. mnevalainen@mcw.edu.
  • # Contributed equally.
PMID: 31548294 DOI: 10.1158/1535-7163.MCT-19-0508
Abstract

The second-generation antiandrogen, enzalutamide, is approved for castrate-resistant prostate Cancer (CRPC) and targets Androgen Receptor (AR) activity in CRPC. Despite initial clinical activity, acquired resistance to enzalutamide arises rapidly and most patients develop terminal disease. Previous work has established STAT5 as a potent inducer of prostate Cancer growth. Here, we investigated the significance of Jak2-Stat5 signaling in resistance of prostate Cancer to enzalutamide. The levels of JAK2 and STAT5 mRNA, proteins and activation were evaluated in prostate Cancer cells, xenograft tumors, and clinical prostate cancers before and after enzalutamide therapy. JAK2 and STAT5 were suppressed by genetic knockdown using lentiviral shRNA or pharmacologic inhibitors. Responsiveness of primary and enzalutamide-resistant prostate Cancer to pharmacologic inhibitors of Jak2-Stat5 signaling was assessed in vivo in mice bearing prostate Cancer xenograft tumors. Patient-derived prostate cancers were tested for responsiveness to STAT5 blockade as second-line treatment after enzalutamide ex vivo in tumor explant cultures. Enzalutamide-liganded AR induces sustained Jak2-Stat5 phosphorylation in prostate Cancer leading to the formation of a positive feed-forward loop, where activated STAT5, in turn, induces Jak2 mRNA and protein levels contributing to further JAK2 activation. Mechanistically, enzalutamide-liganded AR induced JAK2 phosphorylation through a process involving Jak2-specific phosphatases. STAT5 promoted prostate Cancer growth during enzalutamide treatment. Jak2-Stat5 inhibition induced death of prostate Cancer cells and patient-derived prostate cancers surviving enzalutamide treatment and blocked enzalutamide-resistant tumor growth in mice. This work introduces a novel concept of a pivotal role of hyperactivated Jak2-Stat5 signaling in enzalutamide-resistant prostate Cancer, which is readily targetable by JAK2 inhibitors in clinical development.

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