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

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. To identify the histone acetylation alterations that occur with TP53/RB1 loss chromatin reprogramming, we performed H3K27Ac ChIP-seq on TP53/RB1-deficient vs. TP53/RB1-intact cell lines.

ORGANISM(S): Mus musculus

PROVIDER: GSE311404 | GEO | 2026/06/22

REPOSITORIES: GEO

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

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

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 gene expression changes underlying the superior viability effect of the combo treatment, we peformed RNAseq on treated cells.

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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 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.

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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 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

Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma.

Project description: Not available

| S-EPMC5966365 | biostudies-literature

TMPRSS2-ERG suppresses PTEN/TP53 alteration-induced cancer lineage plasticity

Project description:Lineage plasticity is a major mechanism driving prostate cancer progression and antiandrogen therapy resistance. Deletions or mutations in phosphatase and tensin homolog (PTEN) and TP53 tumor suppressor genes have been linked to lineage plasticity in prostate cancer. Fusion-driven overexpression of the E-twenty-six transformation specific (ETS)-related gene (ERG), encoding an oncogenic transcription factor, is observed in approximately 50% of all prostate cancers, yet its role in prostate cell lineage determination remains elusive. Here we demonstrate that transgenic expression of prostate cancer-associated ERG blocks Pten and Trp53 mutation-induced decreased expression of Ar and its downstream target genes and loss of luminal epithelial cell identity in the mouse prostate. Integrative analyses of ERG chromatin-immunoprecipitation sequencing (ChIP-seq) and transcriptome data show that ERG suppresses expression of a subset of cell cycle-promoting genes and RB phosphorylation, which in turn causes repression of E2F1-mediated expression of non-epithelial lineage genes. Xenograft studies show that PTEN/TP53 double mutated prostate tumors are responsive to the cyclin-dependent kinase 4 or 6 (CDK4/6) inhibitor palbociclib, but resistant to the AR inhibitor enzalutamide, while ERG/PTEN/TP53 triple-mutated prostate tumors behave completely opposite. Our studies identify ERG and the repressed cell cycle gene signature as intrinsic inhibitors of PTEN/TP53 double mutation-elicited lineage plasticity in prostate cancer. Our findings also suggest that ERG fusion can be utilized as a biomarker to guide the treatment of PTEN/TP53-mutated, RB1-intact prostate cancer with either antiandrogen or anti-CDK4/6 therapies.

2018-05-16 | GSE103871 | GEO

RB1 loss promotes a noncanonical activator function of LSD1 and sensitizes castration-resistant prostate cancer to LSD1 inhibition [ChIP-seq]

Project description:Genomic loss of RB1 is a common alteration in castration-resistant prostate cancer (CRPC) and is associated with poor patient outcomes. RB1-loss is also a driver event that promotes the neuroendocrine transdifferentiation of prostate cancer (PCa). The loss of Rb protein disrupts the Rb-E2F repressor complex and thus hyperactivates E2F transcription activators. While the impact of RB1-loss on PCa progression and linage plasticity has been previously studied, the underline mechanisms remain unclear. Using an integrated cistromic and transcriptomic analysis, we have characterized Rb activities in multiple CRPC models by identifying Rb directly regulated genes and revealed that Rb has distinct binding sites and targets in TP53-mutated CRPC. Significantly, we show that RB1-loss promotes the noncanonical activator function of LSD1/KDM1A, which stabilizes chromatin binding of E2F1, and hence sensitizes CRPC tumor to the LSD1 inhibitor treatment. These results provide new molecular insights of Rb activity in PCa progression and suggest LSD1 as a potential therapeutic target in CRPC with RB1-loss.

2022-01-14 | GSE176402 | GEO

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