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Updated: Jan 19, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

Published on: March 6, 2018

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Enzalutamide-Induced Feed-Forward Signaling Loop Promotes Therapy-Resistant Prostate Cancer Growth Providing an

Vindhya Udhane1,2,3, Cristina Maranto1,2,3, David T Hoang4

  • 1Department of Pathology, Medical College of Wisconsin Cancer Center, Medical College of Wisconsin, Milwaukee, Wisconsin.

Molecular Cancer Therapeutics
|September 25, 2019
PubMed

Insights

Enzalutamide resistance in prostate cancer involves Jak2-Stat5 signaling. Inhibiting this pathway can overcome resistance and block tumor growth, offering a new therapeutic strategy for advanced prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Enzalutamide is a second-generation antiandrogen used for castrate-resistant prostate cancer (CRPC).
  • Acquired resistance to enzalutamide is a significant clinical challenge, leading to disease progression.
  • Signal transducer and activator of transcription 5 (Stat5) is known to promote prostate cancer growth.

Purpose of the Study:

  • To investigate the role of Janus kinase 2 (Jak2)-Stat5 signaling in enzalutamide resistance in prostate cancer.
  • To evaluate Jak2-Stat5 signaling as a therapeutic target for overcoming enzalutamide resistance.

Main Methods:

  • Assessed Jak2 and Stat5 levels and activation in prostate cancer cells, xenografts, and patient samples before and after enzalutamide treatment.
  • Utilized genetic knockdown (shRNA) and pharmacologic inhibitors to suppress Jak2-Stat5 signaling.
  • Evaluated in vivo tumor growth and ex vivo patient-derived cancer responsiveness to Jak2-Stat5 inhibition.

Main Results:

  • Enzalutamide treatment induced sustained Jak2-Stat5 phosphorylation, forming a positive feedback loop that enhances Jak2 activity.
  • Activated Stat5 promoted prostate cancer growth during enzalutamide treatment.
  • Inhibition of Jak2-Stat5 signaling led to prostate cancer cell death, overcame enzalutamide resistance in patient-derived cancers, and blocked resistant tumor growth in mice.

Conclusions:

  • Hyperactivated Jak2-Stat5 signaling plays a pivotal role in enzalutamide-resistant prostate cancer.
  • Targeting Jak2-Stat5 signaling represents a novel and effective strategy for treating enzalutamide-resistant prostate cancer.
  • Jak2 inhibitors in clinical development show promise for overcoming enzalutamide resistance.

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