Related Experiment Video

Updated: Nov 7, 2025

Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle
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Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle

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Targeting Feedforward Loops Formed by Nuclear Receptor RORγ and Kinase PBK in mCRPC with Hyperactive AR Signaling

Xiong Zhang1, Zenghong Huang1, Junjian Wang1

  • 1Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA 95817, USA.

Cancers
|April 30, 2021
PubMed

Insights

New research identifies RAR-related orphan receptor gamma (RORγ) antagonists as a promising treatment for advanced prostate cancer. Dual inhibition of RORγ and PDZ binding kinase (PBK) shows synergistic effects against aggressive tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive malignancy with limited treatment options.
  • Hyperactive androgen receptor (AR) signaling is a critical driver of CRPC progression.
  • RAR-related orphan receptor gamma (RORγ) was identified as a key regulator of AR gene overexpression.

Purpose of the Study:

  • To investigate the therapeutic potential of RORγ antagonists in mCRPC.
  • To elucidate the downstream targets and signaling pathways regulated by RORγ in prostate cancer.
  • To evaluate the efficacy of combined RORγ and PDZ binding kinase (PBK) inhibition.

Main Methods:

  • Administration of RORγ antagonists (e.g., XY018, compound 31) in preclinical mCRPC models, including patient-derived xenografts (PDX).
  • Analysis of gene expression, protein levels, and signaling pathways, including epithelial-mesenchymal transition (EMT) and invasion markers.
  • Investigation of the interaction between RORγ, AR, and PBK, and the effects of dual inhibition.

Main Results:

  • RORγ antagonists effectively inhibited tumor growth in mCRPC models.
  • RORγ regulates aggressive tumor gene programs, including EMT and invasion.
  • PDZ binding kinase (PBK) was identified as a downstream target of RORγ, and PBK stabilizes RORγ and AR proteins, forming feed-forward loops.
  • Dual inhibition of RORγ and PBK synergistically suppressed RORγ, AR, and AR-V7 expression and function, leading to reduced CRPC cell growth and survival.

Conclusions:

  • RORγ antagonists represent a novel therapeutic strategy for mCRPC.
  • The RORγ-PBK-AR signaling axis is a critical driver of prostate cancer progression.
  • Combined inhibition of RORγ and PBK offers a promising approach for treating advanced prostate cancer.
Keywords:
ARAR-V7CRPCEMTPBKPDXRORγantagonistscell invasioninverse agonistskinasemetastasis

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