Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Combined BET Bromodomain and DNMT Inhibition Targets Lineage Plasticity in Prostate Cancer [BETi_DNMTi_mouse_RNAseq]

ABSTRACT: Lineage plasticity is increasingly recognized as a resistance mechanism to androgen receptor (AR) inhibition in prostate cancer. Loss of the tumor suppressors TP53 and RB1 is common in tumors exhibiting lineage plasticity; however, mechanisms by which TP53/RB1 loss promotes this phenotype remain poorly understood, and effective treatments are limited. Thus we used multi-omic profiling of TP53/RB1 loss prostate cancer models to identify alterations in chromatin accessibility, DNA methylation, and gene expression associated with lineage plasticity. BET bromodomain inhibitors previously were shown to block genes associated with lineage plasticity. We sought to determine whether they could block pathways activated upon TP53/RB1 loss as well. TP53/RB1-deficient cells also harbored widespread DNA methylation changes that silenced pathways linked with lineage plasticity, which we found could be reversed by DNA methyltransferase (DNMT) inhibitors. Combined BET bromodomain and DNMT inhibition was more effective than single agent treatment in suppressing growth in TP53/RB1 loss models compared to single agent treatments. To identify the gene expression changes underlying the superior viability effect of the combo treatment, we peformed RNAseq on treated cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE309033 | GEO | 2026/06/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Combined BET Bromodomain and DNMT Inhibition Targets Lineage Plasticity in Prostate Cancer [ERRBS]

Project description:Lineage plasticity is increasingly recognized as a resistance mechanism to androgen receptor (AR) inhibition in prostate cancer. Loss of the tumor suppressors TP53 and RB1 is common in tumors exhibiting lineage plasticity; however, mechanisms by which TP53/RB1 loss promotes this phenotype remain poorly understood, and effective treatments are limited. Thus we used multi-omic profiling of TP53/RB1 loss prostate cancer models to identify alterations in chromatin accessibility, DNA methylation, and gene expression associated with lineage plasticity. BET bromodomain inhibitors previously were shown to block genes associated with lineage plasticity. We sought to determine whether they could block pathways activated upon TP53/RB1 loss as well. TP53/RB1-deficient cells also harbored widespread DNA methylation changes that silenced pathways linked with lineage plasticity, which we found could be reversed by DNA methyltransferase (DNMT) inhibitors. Combined BET bromodomain and DNMT inhibition was more effective than single agent treatment in suppressing growth in TP53/RB1 loss models compared to single agent treatments. To identify the DNA methylation changes underlying the superior viability effect of the combo treatment, we peformed enhanced reduced representation bisulfite sequencing (ERRBS) on treated cells.

2026-06-22 | GSE311403 | GEO

Combined BET Bromodomain and DNMT Inhibition Targets Lineage Plasticity in Prostate Cancer [ChIP-seq]

2026-06-22 | GSE311404 | GEO

Combined BET Bromodomain and DNMT Inhibition Targets Lineage Plasticity in Prostate Cancer [ATAC-seq]

2026-06-22 | GSE311400 | GEO

Combined BET Bromodomain and DNMT Inhibition Targets Lineage Plasticity in Prostate Cancer

Project description:Lineage plasticity is increasingly recognized as a resistance mechanism to androgen receptor (AR) inhibition in prostate cancer. Neuroendocrine prostate cancer (NEPC) is the most lethal form of lineage plasticity in prostate cancer. BET bromodomain inhibitors (BETi) previously were shown to block genes associated with lineage plasticity. Extensive rewiring of DNA methylation is also associated with NEPC tumors. We sought to determine whether combined BET protein and DNA methyltransferase inhibition (DNMTi) would result in greater anti-tumor activity than single agent treatments alone. To test this, we treated NEPC cell line models with 500nM ZEN (BETi), 100nM dAZA (DNMTi), or the combination daily for 72hrs. We also tested the BETi + DNMTi combination in vivo using an NEPC PDX (LTL331R) with 50mg/kg ZEN and 0.8mg/kg dAZA. Combined BETi and DNMTi was more effective than single agent treatment in suppressing growth in NEPC models compared to single agent treatments. To identify the DNA methylation changes underlying the superior viability effect of the combo treatment, we peformed enhanced reduced representation bisulfite sequencing (ERRBS) on treated cells.

2026-06-22 | GSE311321 | GEO

Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Broad Spectrum of Cancer Therapeutics and Confers Vulnerability to Replication Stress

Project description:Prostate cancers (PC) with loss of the potent tumor suppressors TP53 and RB1 exhibit poor outcomes that include resistance to androgen receptor (AR) pathway antagonists. TP53 and RB1 also influence cell plasticity and are frequently lost in PCs with neuroendocrine (NE) differentiation. Therapeutic strategies that address these aggressive variant PCs are urgently needed. Using deep genomic profiling of 410 metastatic biopsies, we determined the relationships between combined TP53 and RB1 loss and PC phenotypes. Notably, 40% of TP53/RB1 deficient tumors were classified as AR-active adenocarcinomas indicating that NE differentiation is not an obligate consequence of TP53/RB1 inactivation. A gene expression signature reflecting TP53/RB1 loss was associated with diminished responses to AR antagonists and reduced survival. These tumors exhibit high proliferation rates and evidence of elevated DNA repair processes. While tumor cells lacking TP53/RB1 were highly resistant to all single agent therapeutics, the combination of pharmacological PARP and ATR inhibition produced significant responses, reflecting a clinically-exploitable vulnerability resulting from replication stress.

2020-06-01 | GSE147250 | GEO

Combined BET Bromodomain and DNMT Inhibition Targets Lineage Plasticity in Prostate Cancer [BETi_DNMTi_human_RNAseq]

Project description:Lineage plasticity is increasingly recognized as a resistance mechanism to androgen receptor (AR) inhibition in prostate cancer. Neuroendocrine prostate cancer (NEPC) is the most lethal form of lineage plasticity in prostate cancer. BET bromodomain inhibitors (BETi) previously were shown to block genes associated with lineage plasticity. Extensive rewiring of DNA methylation is also associated with NEPC tumors. We sought to determine whether combined BET protein and DNA methyltransferase inhibition (DNMTi) would result in greater anti-tumor activity than single agent treatments alone. To test this, we treated NEPC cell line models with 500nM ZEN (BETi), 100nM dAZA (DNMTi), or the combination daily for 72hrs. We also tested the BETi + DNMTi combination in vivo using an NEPC PDX (LTL331R) with 50mg/kg ZEN and 0.8mg/kg dAZA. Combined BETi and DNMTi was more effective than single agent treatment in suppressing growth in NEPC models compared to single agent treatments. To identify the gene expression changes underlying the superior viability effect of the combo treatment, we peformed RNAseq on treated cells. We also performed RNAseq on a PDX model that reliably transitions from adenocarcinoma (LTL331) to NEPC (LTL331R) in order to uncover the gene expression changes associated with NEPC lineage plasticity and to determine whether BETi and/or DNMTi reverses these gene expression changes.

2026-06-22 | GSE309034 | GEO

Analysis of gene expression (RNAseq) from shTP53:RB1 LNCaP/AR cell lines

Project description:Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. Here we show, using in vitro and in vivo prostate cancer models, that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR) dependent luminal epithelial cells to AR independent basal-like cells. This lineage plasticity is enabled by loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2 and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.

2017-01-06 | GSE89226 | GEO

DNA methylation as a therapeutic target in RB1 deficient and neuroendocrine prostate cancer and rational co-targeting with B7-H3 [22Rv1sgRB1]

Project description:Aberrant DNA methylation has been implicated as a key driver of prostate cancer lineage plasticity and histologic transformation to neuroendocrine prostate cancer (NEPC). DNA methyltransferases (DNMT) are highly expressed, and global DNA methylation levels are elevated in NEPC. We identified that deletion of DNMT genes decreases expression of neuroendocrine lineage markers and markedly reduced NEPC tumor development and metastasis in vivo. Decitabine, a global DNMT inhibitor, significantly attenuated tumor growth in NEPC patient-derived xenograft (PDX) models, as well as RB1-deficient castration-resistant prostate adenocarcinoma (CRPC) models compared with RB1-proficient CRPC. We further discovered that DNMT inhibition increased expression of B7-H3, an emerging druggable target, via demethylation of B7-H3 CpG islands. We tested DS-7300a, a novel antibody-drug conjugate (ADC) targeting B7-H3, alone and in combination with decitabine. There was potent single agent antitumor activity of DS-7300a in both CRPC and NEPC models bearing high expression of B7-H3. In B7-H3 low models, combination therapy of decitabine plus DS-7300a resulted in a synergistic response. Overall, we report that DNMT inhibition is a novel therapeutic target for NEPC and RB1-deficient CRPC and may sensitize B7-H3-low prostate cancer to the ADC DS-7300a through increasing target expression. NEPC and RB1-deficient CRPC represent prostate cancer subgroups with poor prognosis. The development of novel biomarker-driven therapeutic strategies for this population may ultimately help improve patient outcomes.

2024-03-27 | GSE216713 | GEO

DNA methylation as a therapeutic target in RB1 deficient and neuroendocrine prostate cancer and rational co-targeting with B7-H3 [22Rv1sgCD276]

2024-03-27 | GSE216712 | GEO

DNA methylation as a therapeutic target in RB1 deficient and neuroendocrine prostate cancer and rational co-targeting with B7-H3 [RNA-Seq 1]

2024-03-27 | GSE216052 | GEO