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<p>Approximately 50% of prostate cancer (PCa) patients harbor fusions involving the <i>TMPRSS2</i> and <i>ERG</i> genes. Despite this, tailored therapies targeting the fused gene, <i>tERG</i>, remain undeveloped. Our study analyzed biopsy samples from two clinical trials assessing the efficacy of androgen receptor (AR) signaling inhibitors (ARSIs). The results revealed that <i>tERG</i> promotes resistance to ARSIs and is associated with elevated levels of the glucocorticoid receptor (GR). Subsequent assays showed that GR directly interacts with tERG, alleviates allosteric autoinhibition, and prevents chemotherapy-induced tERG degradation. In PCa models, either inhibiting GR or lowering cortisol levels suppressed tumor growth in tERG-positive models, but not in tERG-negative models. In addition, patient-derived fusion-positive xenografts displayed enhanced sensitivity to combined GR and AR inhibitors. Collectively, these findings highlight <i>TMPRSS2-ERG</i> as a new biomarker and propose that simultaneous inhibition of GR and AR may specifically benefit <i>tERG</i>-positive patients. However, GR stimulatory corticosteroid therapies may not be advisable for this patient subgroup.</p>

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TMPRSS2-ERG confers resistance of prostate cancer to antiandrogens

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月12日

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  • Arunachalam Sekar,
  • Boobash Raj Selvadurai,
  • Rishita Chatterjee,
  • Lipika Pal,
  • Aakanksha Verma,
  • Nishanth Belugali Nataraj,
  • Diana Drago Garcia,
  • Suvendu Giri,
  • Alessandro Genna,
  • Feride Karatekin,
  • Nitin Gupta,
  • Deepthi Ramesh-Kumar,
  • Mirie Zerbib,
  • Yaron Vinik,
  • Tamir Avioz,
  • Eviatar Weizman,
  • Eyal David,
  • Alejandro A Schäffer,
  • Yunqian Pan,
  • Haojie Huang,
  • Wytske M van Weerden,
  • Eva Corey,
  • Hazel Hunt,
  • Andrew E Greenstein,
  • Ronnie Blecher-Gonen,
  • Roni Oren,
  • Ariel Afek,
  • Ido Amit,
  • Sima Lev,
  • Anson Ku,
  • Sumeyra Kartal,
  • Jack R Bright,
  • Rosina T Lis,
  • William L Dahut,
  • Adam G Sowalsky,
  • Eytan Ruppin,
  • Yosef Yarden

摘要

Approximately 50% of prostate cancer (PCa) patients harbor fusions involving the TMPRSS2 and ERG genes. Despite this, tailored therapies targeting the fused gene, tERG, remain undeveloped. Our study analyzed biopsy samples from two clinical trials assessing the efficacy of androgen receptor (AR) signaling inhibitors (ARSIs). The results revealed that tERG promotes resistance to ARSIs and is associated with elevated levels of the glucocorticoid receptor (GR). Subsequent assays showed that GR directly interacts with tERG, alleviates allosteric autoinhibition, and prevents chemotherapy-induced tERG degradation. In PCa models, either inhibiting GR or lowering cortisol levels suppressed tumor growth in tERG-positive models, but not in tERG-negative models. In addition, patient-derived fusion-positive xenografts displayed enhanced sensitivity to combined GR and AR inhibitors. Collectively, these findings highlight TMPRSS2-ERG as a new biomarker and propose that simultaneous inhibition of GR and AR may specifically benefit tERG-positive patients. However, GR stimulatory corticosteroid therapies may not be advisable for this patient subgroup.