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TMPRSS2-ERG confers resistance of prostate cancer to antiandrogens

Arunachalam Sekar1, Boobash Raj Selvadurai1, Rishita Chatterjee1

  • 1Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.

EMBO Molecular Medicine
|May 12, 2026
PubMed

Insights

TMPRSS2-ERG gene fusions in prostate cancer (PCa) drive resistance to therapies. Inhibiting the glucocorticoid receptor (GR) alongside the androgen receptor (AR) may benefit tERG-positive PCa patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Approximately 50% of prostate cancer (PCa) cases involve TMPRSS2-ERG gene fusions.
  • Targeted therapies for the resulting tERG fusion protein are currently unavailable.
  • Androgen receptor signaling inhibitors (ARSIs) are a standard treatment for PCa, but resistance is common.

Purpose of the Study:

  • To investigate the role of tERG in ARSI resistance in prostate cancer.
  • To identify potential therapeutic strategies targeting tERG-positive PCa.
  • To explore the interaction between tERG and the glucocorticoid receptor (GR).

Main Methods:

  • Analysis of biopsy samples from patients in clinical trials of ARSIs.
  • Assays to determine the interaction between GR and tERG.
  • In vivo studies using PCa models and patient-derived xenografts.
  • Evaluation of tumor growth inhibition through GR inhibition or cortisol level reduction.

Main Results:

  • tERG was found to promote resistance to ARSIs and correlate with elevated GR levels.
  • GR directly interacts with tERG, stabilizing it against degradation and alleviating autoinhibition.
  • Inhibition of GR or cortisol suppressed tumor growth in tERG-positive PCa models.
  • Patient-derived tERG-positive xenografts showed increased sensitivity to combined GR and AR inhibitors.

Conclusions:

  • TMPRSS2-ERG serves as a potential biomarker for predicting treatment response.
  • Simultaneous inhibition of GR and AR presents a promising therapeutic approach for tERG-positive PCa.
  • Corticosteroid therapies that stimulate GR may be contraindicated in tERG-positive PCa patients.

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