TRIM24 as therapeutic target in endocrine treatment resistant breast cancer (ChIP-Seq)

While ERa+ breast cancer treatment is considered effective, resistance to endocrine therapy is common. Since ERa is still the main driver in most therapy-resistance tumors, alternative therapeutic strategies are needed to disrupt ERa transcriptional activity. In this work, we position TRIM24 as therapeutic target in endocrine resistance, in its role as key player of the ERa transcriptional complex. TRIM24 interacts with ERa and other well-known ERa-cofactors to facilitate ERa chromatin interactions, and allows for maintenance of active histone marks including H3K23ac and H3K27ac. Consequently, genetic perturbation of TRIM24 abrogates ERa-driven transcriptional programs and reduces tumor cell proliferation capacity. Using a recently-developed degrader targeting TRIM24, ERa-driven transcriptional output and growth was blocked, effectively treating not only endocrine-responsive cell lines, but also drug resistant derivates thereof as well as cell line models bearing activating ESR1 point mutations. Finally, using human tumor-derived organoid models, we could show efficacy of TRIM24 degrader in the endocrine responsive and resistant setting. Overall, our study positions TRIM24 as a central component for integrity and activity of the ERa transcriptional complex, with degradation-mediated perturbation of TRIM24 as promising therapeutic avenue in the treatment of primary and endocrine resistance breast cancer. Overall design: ERa and TRIM24 ChIPs in MCF7 WT cells in full-media. 2 biological replicates for ERa ChIPs and 3 biological replicates for TRIM24 ChIPs. ERa, H3K23ac and H3K27ac ChIPs in TRIM24-KO and NT MCF7 cells, in full-media. 3 biological replicates for each ChIP. p-Ser RNA POLII CTD ChIP-seq. Experiment was performed in both TRIM24-KO (clone A and B) and Non-target (NT1 and NT2) MCF7 cells in FBS conditions. 3 biological replicates for each condition was performed. TRIM24 ChIP-seq in MCF7 WT cells treated with DMSO or E2 (10nM) for 3hours