2. Academic Validation
  3. TRIM24 as a therapeutic target in endocrine treatment-resistant breast cancer

TRIM24 as a therapeutic target in endocrine treatment-resistant breast cancer

  • Proc Natl Acad Sci U S A. 2025 Aug 19;122(33):e2507571122. doi: 10.1073/pnas.2507571122.
Nuno Padrão 1,  Sebastian Gregoricchio # 1,  Nils Eickhoff # 1,  Jing Dong 1,  Lara Luzietti 2,  Daniela Bossi 3 4,  Tesa M Severson 1,  Joseph Siefert 1,  Arianna Calcinotto 3 4,  Laki Buluwela 5,  Maria Donaldson Collier 1,  Simak Ali 5,  Leonie Young 6 7,  Jean-Philippe Theurillat 3 4,  Damir Varešlija 2 7,  Wilbert Zwart 1
Affiliations

Affiliations

  • 1 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
  • 2 School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • 3 Institute of Oncology Research, Bellinzona 6500, Switzerland.
  • 4 Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano 6962, Switzerland.
  • 5 Department of Surgery and Cancer, Imperial College London, London SW7 2BX, United Kingdom.
  • 6 Endocrine Oncology Research Group, Department of Surgery, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin D02 YN77, Ireland.
  • 7 Beaumont Royal College of Surgeons in Ireland Cancer Centre, Beaumont Hospital, Dublin D09 V2N0, Ireland.
  • # Contributed equally.
PMID: 40815626 DOI: 10.1073/pnas.2507571122
Abstract

While Estrogen receptor alpha (ERα)+ breast Cancer treatment is considered effective, resistance to endocrine therapy is common. Since ERα is still the main driver in most therapy-resistant tumors, alternative therapeutic strategies are needed to disrupt ERα transcriptional activity. In this work, we position TRIM24 as a therapeutic target in endocrine resistance, given its role as a key component of the ERα transcriptional complex. TRIM24 interacts with ERα and Other well-known ERα cofactors to facilitate ERα chromatin interactions and allows for maintenance of active histone marks including H3K23ac and H3K27ac. Consequently, genetic perturbation of TRIM24 abrogates ERα-driven transcriptional programs and reduces tumor cell proliferation capacity. Using a recently developed degrader targeting TRIM24, ERα-driven transcriptional output and growth were blocked, effectively treating not only endocrine-responsive cell lines but also drug-resistant derivatives thereof as well as cell line models bearing activating ESR1 point mutations. Finally, using human tumor-derived Organoid models, we could show the efficacy of TRIM24 degrader in the endocrine-responsive and -resistant setting. Overall, our study positions TRIM24 as a central component for the integrity and activity of the ERα transcriptional complex, with degradation-mediated perturbation of TRIM24 as a promising therapeutic avenue in the treatment of primary and endocrine resistance breast Cancer.

Keywords

TRIM24; breast cancer; estrogen receptor alpha; heterobifunctional protein degrader; therapy resistance breast cancer.

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