Related Experiment Video

Updated: Dec 23, 2025

Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
07:16

Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor

Published on: September 13, 2018

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IKBKE activity enhances AR levels in advanced prostate cancer via modulation of the Hippo pathway

Alex Bainbridge1, Scott Walker1, Joseph Smith1

  • 1Solid Tumour Target Discovery Laboratory, Translational and Clinical Research Institute, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

Nucleic Acids Research
|April 24, 2020
PubMed

Insights

Targeting IKBKE inhibits androgen receptor (AR) signaling in advanced prostate cancer (PC). This approach circumvents resistance to current therapies and shows promise for repurposing IKBKE inhibitors in castration-resistant PC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Prostate cancer (PC) often develops resistance to androgen receptor (AR) targeting therapies.
  • Mechanisms of resistance include AR amplification and AR splice variants, highlighting AR's continued importance as a therapeutic target.

Purpose of the Study:

  • To investigate the role of IKBKE in driving AR signaling in advanced PC.
  • To evaluate IKBKE inhibition as a strategy to overcome resistance to AR targeting therapies.

Main Methods:

  • Utilized siRNA-mediated IKBKE depletion and pharmacological inhibition in PC cell lines, including enzalutamide-resistant models.
  • Assessed AR gene expression, cell proliferation, migration, and colony formation.
  • Evaluated IKBKE inhibition in a CWR22Rv1 xenograft mouse model and patient-derived explants.
  • Investigated the mechanistic link between IKBKE, Hippo pathway, c-MYC, and AR expression.

Main Results:

  • IKBKE inhibition significantly reduced AR-regulated gene expression and AR expression in vitro and in vivo.
  • Targeting IKBKE suppressed proliferation, migration, and colony formation in resistant PC models.
  • Pharmacological inhibition of IKBKE reduced tumor size and improved survival in mouse models.
  • Validated findings in patient-derived explants, showing reduced proliferation and AR expression upon IKBKE inactivation.

Conclusions:

  • IKBKE drives AR signaling in advanced PC and represents a viable therapeutic target.
  • Targeting IKBKE can circumvent resistance to current AR-targeting therapies.
  • Repurposing clinically tested IKBKE inhibitors may benefit patients with castration-resistant prostate cancer.

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