Targeting feedforward loops formed by nuclear receptor rorγ and kinase PBK in MCRPC with hyperactive ar signaling

Xiong Zhang, Zenghong Huang, Junjian Wang, Zhao Ma, Joy Yang, Eva Corey, Christopher P. Evans, Ai Ming Yu, Hongwu Chen

Research output: Contribution to journalArticlepeer-review

Abstract

Metastatic castration‐resistant prostate cancer (mCRPC) is a highly aggressive disease with few therapeutic options. Hyperactive androgen receptor (AR) signaling plays a key role in CRPC progression. Previously, we identified RAR‐related orphan receptor gamma (RORγ) as a novel key driver of AR gene overexpression and increased AR signaling. We report here that several RORγ antagonists/inverse agonists including XY018 and compound 31 were orally effective in potent inhibition of the growth of tumor models including patient‐derived xenograft (PDX) tumors. RORγ controls the expression of multiple aggressive‐tumor gene programs including those of epi-thelial‐mesenchymal transition (EMT) and invasion. We found that PDZ binding kinase (PBK), a serine/threonine kinase, is a downstream target of RORγ that exerts the cellular effects. Alterations of RORγ expression or function significantly downregulated the mRNA and protein level of PBK. Our further analyses demonstrated that elevated PBK associates with and stabilizes RORγ and AR proteins, thus constituting novel, interlocked feed‐forward loops in hyperactive AR and RORγ sig-naling. Indeed, dual inhibition of RORγ and PBK synergistically inhibited the expression and function of RORγ, AR, and AR‐V7, and the growth and survival of CRPC cells. Therefore, our study provided a promising, new strategy for treatment of advanced forms of prostate cancer.

Original languageEnglish (US)
Article number1672
JournalCancers
Volume13
Issue number7
DOIs
StatePublished - Apr 1 2021

Keywords

  • Antagonists
  • AR
  • AR‐V7
  • Cell invasion
  • CRPC
  • EMT
  • Inverse agonists
  • Kinase
  • Metastasis
  • PBK
  • PDX
  • RORγ

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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