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Updated: Sep 18, 2025

Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses
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Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses

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TMPRSS2-ERG confers resistance to antiandrogens: mechanism and therapeutic implications

Arunachalam Sekar, Rishita Chatterjee, Boobash Raj Selvadurai

    Biorxiv : the Preprint Server for Biology
    |June 26, 2025
    PubMed

    Insights

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

    Area of Science:

    • Oncology
    • Molecular Biology

    Background:

    • Prostate cancer (PCa) frequently involves TMPRSS2-ERG gene fusions.
    • Targeted therapies for the resulting tERG fusion protein are lacking.

    Purpose of the Study:

    • To investigate the role of tERG in resistance to androgen receptor signaling inhibitors (ARSIs).
    • To explore therapeutic strategies targeting tERG-positive PCa.

    Main Methods:

    • Analysis of biopsy samples from clinical trials of ARSIs.
    • Assays to determine interactions between tERG and glucocorticoid receptor (GR).
    • Evaluation of GR inhibition and cortisol reduction in PCa models and xenografts.

    Main Results:

    • tERG promotes resistance to ARSIs and correlates with elevated GR levels.
    • GR directly interacts with tERG, enhancing its stability and function.
    • Inhibition of GR or cortisol suppressed tumor growth in tERG-positive models.
    • Combined GR and AR inhibition showed enhanced efficacy in fusion-positive xenografts.

    Conclusions:

    • TMPRSS2-ERG is a potential biomarker for ARSI resistance in prostate cancer.
    • Simultaneous inhibition of GR and AR may be a targeted therapy for tERG-positive PCa.
    • Corticosteroid therapies may be contraindicated for tERG-positive patients.

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