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Endosomal recycling inhibitors downregulate the androgen receptor and synergise with enzalutamide

Kelsey A Fletcher1, Mai H Alkurashi1, Andrew J Lindsay2

  • 1Membrane Trafficking and Disease Laboratory, School of Biochemistry & Cell Biology, Biosciences Institute, University College Cork, Cork, T12 YT20, Ireland.

Investigational New Drugs
|November 13, 2023
PubMed

Insights

Targeting endosomal recycling may overcome drug resistance in prostate cancer. Inhibitors downregulate androgen receptor (AR) and synergize with enzalutamide, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Prostate cancer is a leading cause of cancer death worldwide.
  • Drug-resistant metastatic prostate cancer remains a significant clinical challenge.
  • Novel therapeutic strategies are needed to overcome treatment resistance.

Purpose of the Study:

  • To investigate targeting the endosomal recycling pathway as a novel therapeutic strategy for prostate cancer.
  • To determine the effect of endosomal recycling inhibitors on androgen receptor (AR) expression in prostate cancer cells.
  • To evaluate the synergistic effect of endosomal recycling inhibitors with enzalutamide.

Main Methods:

  • Utilized reverse phase protein array (RPPA) assays.
  • Treated breast and prostate cancer cells with endosomal recycling inhibitors.
  • Analyzed androgen receptor (AR) expression at the transcriptional level.
  • Assessed the synergy between endosomal recycling inhibitors and enzalutamide.

Main Results:

  • Endosomal recycling inhibitors significantly downregulated androgen receptor (AR) in prostate cancer cells.
  • AR downregulation by these inhibitors occurs at the transcriptional level.
  • Endosomal recycling inhibitors demonstrated synergistic effects when combined with enzalutamide.

Conclusions:

  • Targeting the endosomal recycling pathway is a promising strategy to downregulate AR in prostate cancer.
  • Combining endosomal recycling inhibitors with enzalutamide may enhance treatment efficacy.
  • This approach could potentially reduce the emergence of drug resistance in prostate cancer therapy.
Keywords:
Androgen receptorHER3Receptor recyclingSmall molecules

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