TMPRSS2-ERG confers resistance of prostate cancer to antiandrogens
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.
Authors
- Alejandro A. Schäffer (ORCID: https://orcid.org/0000-0002-2147-8033)
- Roni Oren (ORCID: https://orcid.org/0000-0003-1228-412X)
- Yaron Vinik (ORCID: https://orcid.org/0000-0003-3344-5922)
- Yunqian Pan (ORCID: https://orcid.org/0000-0003-0912-8978)
- Aakanksha Verma (ORCID: https://orcid.org/0000-0001-9827-9457)
- Alessandro Genna (ORCID: https://orcid.org/0000-0003-4821-1491)
- Wytske M. van Weerden (ORCID: https://orcid.org/0000-0003-0324-4804)
- Ariel Afek (ORCID: https://orcid.org/0000-0001-8584-9879)
- Andrew E. Greenstein (ORCID: https://orcid.org/0000-0002-1470-1970)
- Jack Bright
- William L. Dahut (ORCID: https://orcid.org/0000-0002-2766-9703)
- Eyal David (ORCID: https://orcid.org/0000-0002-9020-2364)
- Suvendu Giri (ORCID: https://orcid.org/0000-0002-7595-1359)
- Diana Drago-García (ORCID: https://orcid.org/0000-0001-6397-3123)
- Mirie Zerbib
- Adam G. Sowalsky (ORCID: https://orcid.org/0000-0003-2760-1853)
- Ido Amit (ORCID: https://orcid.org/0000-0003-2968-877X)
- Sima Lev (ORCID: https://orcid.org/0000-0002-2108-3330)
- Rosina T. Lis (ORCID: https://orcid.org/0000-0002-5237-5299)
- Rishita Chatterjee (ORCID: https://orcid.org/0000-0001-8484-3897)
- Arunachalam Sekar (ORCID: https://orcid.org/0000-0002-4659-5260)
- Ronnie Blecher‐Gonen (ORCID: https://orcid.org/0000-0003-2847-1149)
- Nishanth Belugali Nataraj (ORCID: https://orcid.org/0000-0003-2970-6739)
- Sumeyra Kartal (ORCID: https://orcid.org/0000-0002-6728-7080)
- Deepthi Ramesh (ORCID: https://orcid.org/0000-0002-8987-2213)
- Feride Karatekin (ORCID: https://orcid.org/0009-0009-5430-429X)
- Tamir Avioz
- Boobash Raj Selvadurai
- Eviatar Weizman
- Haojie Huang (ORCID: https://orcid.org/0000-0003-2751-6413)
- Eva Corey (ORCID: https://orcid.org/0000-0002-9244-3807)
- Lipika Pal
- Eytan Ruppin (ORCID: https://orcid.org/0000-0002-7862-3940)
- Yosef Yarden (ORCID: https://orcid.org/0000-0001-8578-0250)
- Anson Ku
- Nitin Gupta (ORCID: https://orcid.org/0000-0001-6485-6113)
- Hazel Hunt
Institutions
- National Institutes of Health (US)
- Mayo Clinic (US)
- Exelixis (United States) (US)
- University of Washington (US)
- The Francis Crick Institute (GB)
- Erasmus MC (NL)
- Cellworks Research (India) (IN)
- Corcept Therapeutics (United States) (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- Weizmann Institute of Science (IL)
- Institute of Molecular and Cell Biology (SG)
Publication Details
- Journal
- EMBO Molecular Medicine
- Published
- 2026-05-12
- DOI
- https://doi.org/10.1038/s44321-026-00423-7
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Israel Cancer Research Fund
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Institut National de la Santé et de la Recherche Médicale
- Israel Science Foundation
- Tel Aviv University
- Université Paris Descartes
- National Institutes of Health
- European Research Council
- National Cancer Institute
- Intramural Research Program