BET bromodomain inhibition blocks the function of a critical AR-independent master regulator network in lethal prostate cancer

Coleman, Daniel J.; Gao, Lina; King, Carly J.; Schwartzman, Jacob; Urrutia, Joshua A.; Sehrawat, Archana; Tayou, Junior; Balter, Ariel; Burchard, Julja; Chiotti, Kami; Derrick, Daniel S.; Sun, Duanchen; Xia, Zheng; Heiser, Laura M.; Alumkal, Joshi J.

doi:10.1038/s41388-019-0815-5

Cited by 25 publications

(19 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Prior work demonstrated that BETi is a promising approach to block growth of AR-driven tumors (37), and we recently extended these findings and confirmed the anti-tumor activity of BETi in AR-null adenocarcinoma CRPC (34,38). Thus, we sought to determine the anti-tumor These LuCaP cultures do not proliferate well long-term, but BETi treatment using concentrations < 1 µM of either agent led to cell death (Supplemental Figure S5G).…”

Section: Bet Bromodomain Inhibition Blocks E2f1 Function T-nepc Lineage Plasticity Gene Expression and T-nepc Cell Survivalmentioning

confidence: 60%

“…The anti-tumor activity of BETi in CRPC has been primarily linked to suppression of AR function (37,49). However, we recently demonstrated that BETi also blocks the growth of ARnull adenocarcinoma CRPC tumors in pre-clinical studies (34,38) and growth of patient tumors that responded poorly to enzalutamide or abiraterone-many of which are AR activity-low (40).…”

Section: Discussionmentioning

confidence: 99%

“…BET bromodomain proteins cooperate with specific master regulator transcription factors to promote gene expression and lineage commitment (33,34). To identify factors that may cooperate with BRD4, we first performed functional enrichment analysis of the shared H3K27ac and BRD4 peaks in the enzalutamide condition.…”

Section: The Chromatin State Of Enzalutamide-resistant T-nepc Cells Is Conducive To Lineage Plasticity Gene Expressionmentioning

confidence: 99%

See 2 more Smart Citations

BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

Kim

Sun

Storck

et al. 2021

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Lineage plasticity in prostate cancer-most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program-is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently there are limited treatments for NEPC. Moreover, the incidence of treatment-emergent NEPC (t-NEPC) is increasing in the era of novel AR inhibitors. In contradistinction to de novo NEPC, t-NEPC tumors often express the AR, but AR's functional role in t-NEPC is unknown.Furthermore, targetable factors that promote t-NEPC lineage plasticity are also unclear.Experimental Design: Using an integrative systems biology approach, we investigated enzalutamide-resistant t-NEPC cell lines and their parental, enzalutamide-sensitive adenocarcinoma cell lines. The AR is still expressed in these t-NEPC cells, enabling us to determine the role of the AR and other key factors in regulating t-NEPC lineage plasticity.Results: AR inhibition accentuates lineage plasticity in t-NEPC cells-an effect not observed in parental enzalutamide-sensitive adenocarcinoma cells. Induction of an AR-repressed, lineage plasticity program is dependent on activation of the transcription factor E2F1 in concert with the BET bromodomain chromatin reader BRD4. BET inhibition (BETi) blocks this E2F1/BRD4regulated program and decreases growth of t-NEPC tumor models and a subset of t-NEPC patient tumors with high activity of this program in a BETi clinical trial.Conclusions: E2F1 and BRD4 are critical for activating an AR-repressed t-NEPC lineage plasticity program. BETi is a promising approach to block this program.Research.

show abstract

Section: Bet Bromodomain Inhibition Blocks E2f1 Function T-nepc Lineage Plasticity Gene Expression and T-nepc Cell Survivalmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: The Chromatin State Of Enzalutamide-resistant T-nepc Cells Is Conducive To Lineage Plasticity Gene Expressionmentioning

confidence: 99%

See 1 more Smart Citation

BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

Kim

Sun

Storck

et al. 2021

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Recent data in pre-clinical studies revealed that BET inhibitors exert potential anti-tumor effects in non-small cell lung cancer cells [27], mixed-lineage leukemia gene-fused leukemia [28], and other solid tumors including pancreatic ductal adenocarcinoma [29], prostate cancer [30]. In several subtypes of breast cancer, BET inhibitors have been shown to display a strong anti-tumor effect.…”

Section: Discussionmentioning

confidence: 99%

IKBKE is a critical mediator of TAM-induced breast cancer resistance to BET inhibition

Qiao¹,

Chen²,

Mi³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: BET inhibitors (BETi) exhibit a strong anti-tumor activity in triple-negative breast cancer (TNBC). However, BETi resistance has been reported in TNBC. The mechanisms of resistance have not been demonstrated. Tumor-associated macrophages (TAMs) are frequently involved in cancer cells resistance to chemotherapy, also associated with poor prognosis in TNBC. However, the role of TAMs in BETi resistance remains unknown. Method: The expression of RNA was evaluated by qRT-PCR. Protein was detected by Western blot, immunofluorescence and Enzyme linked immunosorbent assay (ELISA). Cell viability was detected by Cell Counting Kit-8 (CCK-8). Apoptosis was evaluated by Annexin V-FITC/PI, TUNEL assays and Hoechst 33258 staining. NF-κB activities were detected by luciferase reporter assays. Mice model of breast cancer was established with subcutaneous xenograft tumor. Detailed mechanistic studies were performed by using inhibitors, RNA interference and DNA transfections. Results: Here, we found that BETi JQ1 and I-BET151 exerted anti-tumor effects in TNBC by decreasing IKBKE expression to attenuate NF-κB signaling. BET inhibition was found to downregulate IKBKE levels through BRD2/E2F1 axis. Moreover, we firstly found that TNBC-stimulated TAMs activated NF-κB signaling by upregulating IKBKE expression to enhance breast cancer cells resistance to BETi. The IKBKE levels were also proved to be higher in clinical TNBC tissues than Non-TNBC tissues, suggesting feedback induction of IKBKE expression by TNBC-stimulated TAMs in TNBC. In addition, the induction of IKBKE by TAMs in TNBC cells was identified to be associated with STAT3 signaling, which was activated by TAM-secreted IL-6 and IL-10. Lastly, the combination of inhibitors of BET and STAT3 exerted a synergistic inhibition effects in TAM-cocultured or TAM CM-treated TNBC cells in vitro and in vivo . Conclusion: Altogether, our findings illustrated TNBC-activated macrophages conferred TNBC cells resistance to BETi via IL-6 or IL-10/STAT3/IKBKE/NF-κB axis. Blockade of IKBKE or double inhibition of BET and STAT3 might be a novel strategy for treatment of TNBC.

show abstract

“…Treatment with EP300/CREBBP inhibitors not only reduced AR but also MYC signaling. 51 Although the current study focused on inhibition of EP300/CREBBP in association with MYC/ribosomal protein regulation, other possible actions of these inhibitors should be mentioned. Recently, Fan et al 52 reported that enzalutamide-resistant C4-2 cells are more sensitive to either BET or EP300/CREBBP inhibitors than parental cells.…”

Section: Ribosomal Proteins In Prostate Cancermentioning

confidence: 98%

MYC-Mediated Ribosomal Gene Expression Sensitizes Enzalutamide-resistant Prostate Cancer Cells to EP300/CREBBP Inhibitors

Furlan

Kirchmair

Sampson

et al. 2021

The American Journal of Pathology

View full text Add to dashboard Cite

BET bromodomain inhibition blocks the function of a critical AR-independent master regulator network in lethal prostate cancer

Cited by 25 publications

References 43 publications

BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program

IKBKE is a critical mediator of TAM-induced breast cancer resistance to BET inhibition

MYC-Mediated Ribosomal Gene Expression Sensitizes Enzalutamide-resistant Prostate Cancer Cells to EP300/CREBBP Inhibitors

Contact Info

Product

Resources

About