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Enzalutamide-Induced Feed-Forward Signaling Loop Promotes Therapy-Resistant Prostate Cancer Growth Providing an Exploitable Molecular Target for Jak2 Inhibitors. Mol Cancer Ther 2020 01;19(1):231-246

Date

09/25/2019

Pubmed ID

31548294

Pubmed Central ID

PMC6946850

DOI

10.1158/1535-7163.MCT-19-0508

Scopus ID

2-s2.0-85077669370   10 Citations

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.

Author List

Udhane V, Maranto C, Hoang DT, Gu L, Erickson A, Devi S, Talati PG, Banerjee A, Iczkowski KA, Jacobsohn K, See WA, Mirtti T, Kilari D, Nevalainen MT

Authors

Anjishnu Banerjee PhD Associate Professor in the Institute for Health and Equity department at Medical College of Wisconsin
Kenneth A. Iczkowski MD Professor in the Pathology department at Medical College of Wisconsin
Deepak Kilari MD Associate Professor in the Medicine department at Medical College of Wisconsin
Marja T. Nevalainen MD, PhD Assistant Dean, Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Benzamides
Humans
Janus Kinase 2
Male
Mice
Mice, Nude
Nitriles
Phenylthiohydantoin
Prostatic Neoplasms, Castration-Resistant
Signal Transduction
Xenograft Model Antitumor Assays