Discovery of Selective and Potent BRPF1 Dege-reraders for the Treatment of Endocrine-sensitive Breast Cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo Sapiens
SUBMITTER: 
Yubo Zhou
PROVIDER: PXD080650 | iProX | Mon Jul 06 00:00:00 BST 2026
REPOSITORIES: iProX
Similar Datasets
Project description:While ERα+ breast cancer treatment is considered effective, resistance to endocrine therapy is common. Since in therapy-resistance tumors, ERα is still the main driver, alternative therapeutic strategies are needed to disrupt ERα transcriptional activity. In this work, we describe TRIM24 as a key player 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 PROTAC targeting TRIM24, ERα-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 ERα-negative organoids. Overall, our study positions TRIM24 as a central component for integrity and activity of the ERα transcriptional complex, with PROTAC-mediated perturbation of TRIM24 as promising therapeutic avenue in the treatment of primary and endocrine resistance breast cancer.
2025-08-01 | PXD046736 | Pride
Project description:While ERα+ breast cancer treatment is considered effective, resistance to endocrine therapy is common. Since in therapy-resistance tumors, ERα is still the main driver, alternative therapeutic strategies are needed to disrupt ERα transcriptional activity. In this work, we describe TRIM24 as a key player 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 PROTAC targeting TRIM24, ERα-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 ERα-negative organoids. Overall, our study positions TRIM24 as a central component for integrity and activity of the ERα transcriptional complex, with PROTAC-mediated perturbation of TRIM24 as promising therapeutic avenue in the treatment of primary and endocrine resistance breast cancer.
2025-08-01 | GSE246793 | GEO
Project description:Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that co- ordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-kB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treat- ment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.
2024-05-23 | PXD043560 | Pride
Project description:Bromodomain extraterminal protein (BETP) inhibitors transcriptionally repress oncoproteins which undermines the growth and survival of AML cells. However, BETi treatment causes accumulation of BETPs, associated with reversible binding and incomplete inhibition of BRD4, which potentially compromises the activity of BETi in AML cells. Unlike BETi, BET-PROTAC (proteolysis-targeting chimera) ARV-825 recruits and utilize an E3-ubiquitin ligase to effectively degrade BETPs in AML cells. BET-PROTACs induce more apoptosis than BETi of mtRUNX1 AML cells. BET-PROTAC treatment induced more perturbations in the mRNA and protein expressions than BETi. It was noted that treatment with BETi or BET-PROTAC caused significant and sustained depletion of RUNX1 in AML cells. We also determined the effects of global depletion of RUNX1 in mtRUNX1 expressing AML OCI-AML5 cells. We observed an overlap in the signature of RUNX1 knockdown by shRNA with that of OTX015 and ARV-825 in OCI-AML5 cells.
2020-08-11 | GSE119261 | GEO
Project description:The mammalian SWI/SNF helicase SMARCA4 is frequently mutated in cancer and inactivation results in a cellular dependence on its paralog, SMARCA2, thus making SMARCA2 an attractive synthetic lethal target. However, published data indicates that achieving a high degree of SMARCA2 selectivity is likely essential to afford an acceptable therapeutic index and this has been a considerable challenge due to the homology between paralogs. Herein we report the discovery of the first potent and selective SMARCA2 proteolysis-targeting chimera (PROTAC) molecule. Selective degradation was achieved in the absence of selective PROTAC binding and translated to potent in vitro growth inhibition and in vivo efficacy in SMARCA4 mutant models, compared to wild type models. Global ubiquitin mapping and proteome profiling revealed no unexpected off-target degradation. Our study thus highlights the ability to transform a non-selective SMARCA2-binding ligand into a selective and efficacious in vivo SMARCA2 PROTAC, providing a potential therapeutic opportunity for SMARCA4 mutant patients.
2022-09-22 | PXD036865 | Pride
Project description:To support cellular homeostasis and mitigate chemotherapeutic stress, cancer cells must gain a series of adaptive intracellular processes. Here we identify that NUPR1, a tamoxifen (Tam)-induced transcriptional coregulator, is necessary for the maintenance of Tam resistance through physical interaction with ESR1 in breast cancers. Mechanistically, NUPR1 binds to the promoter regions of several genes involved in autophagy process and drug resistance such as BECN1, GREB1, RAB31, PGR, CYP1B1, and regulates their transcription. In Tam-resistant ESR1 breast cancer cells, NUPR1 depletion results in premature senescence in vitro and tumor suppression in vivo. Moreover, enforced-autophagic flux augments cytoplasmic vacuolization in NUPR1-depleted Tam resistant cells, which facilitates the transition from autophagic survival to premature senescence. Collectively, these findings suggest a critical role for NUPR1 as a transcriptional coregulator in enabling endocrine persistence of breast cancers, thus providing a vulnerable diagnostic and/or therapeutic target for endocrine resistance.
2018-04-27 | GSE104050 | GEO
Project description:Luminal A breast cancer is characterized by the expression and activity of estrogen receptor-α (ERα), a biomarker and therapeutic target. While endocrine therapies targeting ER signaling have shown efficacy, long-term success is limited by the development of resistance. Almost 40% of ER-positive breast cancer patients presenting with late-stage disease either fail to respond to endocrine therapies or relapse due to acquired resistance, leading to poor prognosis. Here, we focused on aromatase inhibition, which is administered to patients in menopause, and found strong upregulation of GLYATL1 (glutamine-N-acyltransferase) in two endocrine therapy-resistant in vitro models. Increased expression of GLYATL1 was found also in patients during treatment and its expression was significantly correlated with poor survival in luminal A breast cancer patients after administration of aromatase inhibitors. Interference with GLYATL1 reversed the resistance phenotype in both in vitro models. GLYATL1 expression was associated with overall decreased TCA cycle activity, however, accumulation of succinate, and with altered histone modifications. Unexpectedly, GLYATL1 expression was found to be positively regulated by estrogen-receptor, yet only in estrogen-deprived conditions suggesting that GLYATL1 is a novel factor in endocrine therapy-resistance of luminal breast cancer, impinging on metabolism and epigenetic gene regulation.
2026-01-30 | PXD067936 | Pride
Project description:Neurofibromin/NF1-depletion (NF1low) is associated with endocrine therapy resistance in approximately 20% of ER+/HER2– early-stage breast cancer but specific treatments for NF1low tumors are not established. Proteogenomic analyses on ER+/HER2– breast cancer demonstrated that NF1low tumors exhibit elevated CDK4/6 activity. NF1-silencing in cell lines promoted ER recruitment to CCND1, thus increasing cyclin-D1 levels. Additionally, RAF is demonstrated to directly phosphorylate the CDK4 activation-loop (pT172) thus providing a direct connection between NF1 loss and an increase in CDK4 activity. Consequently, NF1low cancer cells are differentially sensitive to a fulvestrant plus CDK4/6 inhibitor (CDK4/6i) combination, with cell-death induction in vitro, and durable tumor regressions in ER+ NF1low PDX models in vivo. Furthermore, NF1low ER+/HER2– tumors treated neoadjuvantly with 4 weeks of anastrozole exhibited a minimal reduction of a multigene mRNA proliferation score vs NF1high tumors but exhibited marked sensitivity to the subsequent addition of palbociclib. In conclusion, dual ER and downstream RAF activation following NF1-loss drives endocrine therapy resistance and CDK4/6i sensitivity in NF1low ER+ breast cancer. NF1 status should therefore be prioritized for biomarker investigations in adjuvant CDK4/6i trials to determine whether the NF1low status
2025-12-15 | PXD052290 | Pride
Project description:Around two thirds of breast tumors are characterized by the expression of estrogen receptor α and are therapeutically treated by blocking estrogen signaling. First line endocrine therapeutics are Tamoxifen which displaces estrogen form its receptor preventing receptor activation and aromatase inhibitors which prevent the formation of estrogen and thereby hormone-deprive the tumors. Therapy resistance remains a major clinical problem, especially for patients with late-stage diagnoses. Tumor heterogeneity may promote therapy resistance either through the selection of pre-existing rare clones or by providing a repertoire of cells that may develop resistance over time. In order to study endocrine therapy resistance on a clonal level, we have developed barcoded (allowing the tracking of single cells) endocrine therapy sensitive and resistant breast cancer cell lines. From these complex cell pools, multiple single cells characterized by a specific barcode were isolated and grown out. We then subjected the clones to phosphoproteomics measurement by Mass spectrometry. Based on their phosphorylation pattern, the kinase activity profiles of endocrine therapy resistant clones were determined to identify differentially activated kinases with implications in therapy resistance.
2024-01-26 | PXD040478 | Pride
Project description:The mammalian SWI/SNF helicase SMARCA4 is frequently mutated in cancer and inactivation results in a cellular dependence on its paralog, SMARCA2, thus making SMARCA2 an attractive synthetic lethal target. However, published data indicates that achieving a high degree of SMARCA2 selectivity is likely essential to afford an acceptable therapeutic index and this has been a considerable challenge due to the homology between paralogs.
Herein we report the discovery of the first potent and selective SMARCA2 proteolysis-targeting chimera (PROTAC) molecule. Selective degradation was achieved in the absence of selective PROTAC binding and translated to potent in vitro growth inhibition and in vivo efficacy in SMARCA4 mutant models, compared to wild type models. Global ubiquitin mapping and proteome profiling revealed no unexpected off-target degradation. Our study thus highlights the ability to transform a non-selective SMARCA2-binding ligand into a selective and efficacious in vivo SMARCA2 PROTAC, providing a potential therapeutic opportunity for SMARCA4 mutant patients.
2022-03-31 | MSV000089176 | MassIVE