TRIM24 as a therapeutic target in endocrine treatment-resistant breast cancer
Nuno Padrão1, Sebastian Gregoricchio1, Nils Eickhoff1
1Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
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.
Insights
TRIM24 is a key protein in Estrogen receptor alpha (ERα) activity. Targeting TRIM24 with a degrader effectively treats ERα-positive breast cancer, including endocrine-resistant and ESR1-mutated forms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Endocrine therapy resistance is a major challenge in Estrogen receptor alpha (ERα)-positive breast cancer.
- ERα remains the primary driver in many therapy-resistant tumors, necessitating novel therapeutic strategies.
- Targeting ERα transcriptional activity is crucial for overcoming resistance.
Purpose of the Study:
- To investigate TRIM24 as a potential therapeutic target in endocrine-resistant breast cancer.
- To elucidate the role of TRIM24 in the ERα transcriptional complex and its impact on tumor growth.
- To evaluate the efficacy of a TRIM24 degrader in preclinical models of breast cancer.
Main Methods:
- Investigated TRIM24's interaction with ERα and cofactors.
- Assessed the effect of genetic TRIM24 perturbation on ERα-driven transcription and cell proliferation.
- Utilized a TRIM24 degrader in endocrine-responsive, drug-resistant, and ESR1-mutated cell line models.
- Validated TRIM24 degrader efficacy in human tumor-derived organoid models.
Main Results:
- TRIM24 facilitates ERα chromatin interactions and maintains active histone marks (H3K23ac, H3K27ac).
- Genetic disruption of TRIM24 inhibits ERα transcriptional programs and reduces tumor cell proliferation.
- TRIM24 degrader treatment blocked ERα output and growth in various resistant models, including those with ESR1 mutations.
- TRIM24 degrader demonstrated efficacy in both endocrine-responsive and -resistant human tumor organoids.
Conclusions:
- TRIM24 is essential for the integrity and activity of the ERα transcriptional complex.
- Degradation of TRIM24 represents a promising therapeutic strategy for primary and endocrine-resistant breast cancer.
- Targeting TRIM24 offers a novel approach to overcome endocrine therapy resistance in ERα-positive breast cancer.
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