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

• 成果类型: Article
• 署名作者: Padrao, Nuno; Gregoricchio, Sebastian; Eickhoff, Nils; Dong, Jing; Luzietti, Lara; Bossi, Daniela; Severson, Tesa M.; Siefert, Joseph; Calcinotto, Arianna; Buluwela, Laki; Collier, Maria Donaldson; Ali, Sima; Young, Leoni; Theurillat, Jean-Philippe; Varestija, Damir; Zwart, Wilbert
• 署名单位: Netherlands Cancer Institute; Royal College of Surgeons - Ireland; Institute of Oncology Research (IOR); Universita della Svizzera Italiana; Imperial College London; Royal College of Surgeons - Ireland; Beaumont Hospital Dublin
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8444
• DOI: 10.1073/pnas.2507571122
• 发表日期: 2025-08-19
• 关键词: estrogen-receptor; metastatic progression; binding; alpha; inhibitors; alignment; mediator; reveals; foxa1; DRUG

摘要

While Estrogen receptor alpha (ER alpha)+ breast cancer treatment is considered effective, resistance to endocrine therapy is common. Since ER alpha is still the main driver in most therapy-resistant tumors, alternative therapeutic strategies are needed to disrupt ER alpha transcriptional activity.In this work, we position TRIM24 as a therapeutic target in endocrine resistance, given its role as a key component of the ER alpha transcriptional complex. TRIM24 interacts with ER alpha and other well-known ER alpha cofactors to facilitate ER alpha chromatin interactions and allows for maintenance of active histone marks including H3K23ac and H3K27ac. Consequently, genetic perturbation of TRIM24 abrogates ER alpha-driven transcriptional programs and reduces tumor cell proliferation capacity. Using a recently developed degrader targeting TRIM24, ER alpha-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 ER alpha transcriptional complex, with degradation-mediated perturbation of TRIM24 as a promising therapeutic avenue in the treatment of primary and endocrine resistance breast cancer.