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

While ERa+ breast cancer treatment is considered effective, resistance to endocrine therapy is common. Since in therapy-resistance tumors, ERa is still the main driver, alternative therapeutic strategies are needed to disrupt ERa transcriptional activity. In this work, we describe TRIM24 as a 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 PROTAC 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 PROTAC in the endocrine responsive and resistant setting, with no response in ERa-negative organoids. Overall, our study positions TRIM24 as a central component for integrity and activity of the ERa transcriptional complex, with PROTAC-mediated perturbation of TRIM24 as promising therapeutic avenue in the treatment of primary and endocrine resistance breast cancer. Overall design: RNA-seq in MCF7 TRIM24-KO (clone A and B) and NT (clone 1 and 2) cells in full-media. 3 biological replicates. RNA-seq in MCF7 WT cells treated with either 5µM of dTRIM24 (TRIM24 PROTAC, HY-111519) or vehicle (DMSO) in full-media. 3 biological replicates.