GSK2801, a BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer

Bevill, Samantha M.; Olivares-Quintero, José F.; Sciaky, Noah; Golitz, Brian T.; Singh, Darshan; Beltran, Adriana S.; Rashid, Naim U.; Stuhlmiller, Timothy J.; Hale, Andrew; Moorman, Nathaniel J.; Santos, Charlene; Zawistowski, Jon S.; Johnson, Gary L.

doi:10.1158/1541-7786.mcr-18-1121

Cited by 50 publications

(53 citation statements)

References 57 publications

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“…3 ). Antiproliferative synergy has also been observed in triple negative breast cancer when the bromodomains of BRD9 and bromodomain adjacent zinc finger BAZ2A are inhibited concurrently [ 129 ]. In addition, there appears to be a connection between splicing factor protein SF3B1 mutations and BRD9 degradation in cancers like myeloid leukemia, lymphoid leukemia, and uveal melanoma [ 130 ].…”

Section: Gbaf and Its Subunits In Mammalian Diseasementioning

confidence: 99%

GBAF, a small BAF sub-complex with big implications: a systematic review

Innis

Cabot

2020

Epigenetics & Chromatin

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ATP-dependent chromatin remodeling by histone-modifying enzymes and chromatin remodeling complexes is crucial for maintaining chromatin organization and facilitating gene transcription. In the SWI/SNF family of ATP-dependent chromatin remodelers, distinct complexes such as BAF, PBAF, GBAF, esBAF and npBAF/nBAF are of particular interest regarding their implications in cellular differentiation and development, as well as in various diseases. The recently identified BAF subcomplex GBAF is no exception to this, and information is emerging linking this complex and its components to crucial events in mammalian development. Furthermore, given the essential nature of many of its subunits in maintaining effective chromatin remodeling function, it comes as no surprise that aberrant expression of GBAF complex components is associated with disease development, including neurodevelopmental disorders and numerous malignancies. It becomes clear that building upon our knowledge of GBAF and BAF complex function will be essential for advancements in both mammalian reproductive applications and the development of more effective therapeutic interventions and strategies. Here, we review the roles of the SWI/SNF chromatin remodeling subcomplex GBAF and its subunits in mammalian development and disease.

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Section: Gbaf and Its Subunits In Mammalian Diseasementioning

confidence: 99%

GBAF, a small BAF sub-complex with big implications: a systematic review

Innis

Cabot

2020

Epigenetics & Chromatin

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“…In BRCA1-deficient breast cancer, BET inhibitors induce DNA damage and kill cancer cells by elevating cellular oxidative stress [31]. In TNBC, BET inhibitors exert anti-tumor functions by blocking cell proliferation, inducing cell apoptosis and inhibiting angiogenesis [5,7,[32][33][34]. Moreover, BET inhibitors have been reported to enhance the effect of immunotherapy by suppressing transcriptional expression of MYC in TNBC [35].…”

Section: Discussionmentioning

confidence: 99%

“…By constructing the cell lines selected for acquired resistance to BET inhibition, they clarified the mechanisms of BETi resistance in TNBC [6]. Recently, several studies reported that BET inhibitors combined with other agents such as BAZ2/BRD9 inhibitor GSK2801, Bcl-XL inhibitor and vitamin C exert synergistic effect in ducing TNBC cells apoptosis [7][8][9]. Moreover, currently several clinical trials with BETi have been approved for cancer treatment.…”

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confidence: 99%

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

Qiao¹,

Chen²,

Mi³

et al. 2020

Preprint

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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.

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“…Targeting Brd9 is possible and in vivo active inhibitors are available [112]. It has been attempted in vitro in rhabdoid tumours [113] and in vivo in other entities [114].…”

Section: The Epigenetic Consequences Of Smarcb1 Alterationsmentioning

confidence: 99%

Invited Review: Dysregulation of chromatin remodellers in paediatric brain tumours – SMARCB1 and beyond

Johann

2020

Neuropathology Appl Neurobio

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2020) Neuropathology and Applied Neurobiology 46, 57-72 Dysregulation of chromatin remodellers in paediatric brain tumours -SMARCB1 and beyond Mutations in chromatin remodelling genes occur in approximately 25% of all human tumours (Kadoch et al. Nat Genet 45: 592-601, 2013). The spectrum of alterations is broad and comprises single nucleotide variants, insertion/deletions and more complex structural variations. The single most often affected remodelling complex is the SWI/SNF complex (SWItch/sucrose non-fermentable). In the field of paediatric neuro-oncology, the spectrum of affected genes implicated in epigenetic remodelling is narrower with SMARCB1 and SMARCA4 being the most frequent.The low mutation frequencies in many of the SWI/SNF mutant entities underline the fact that perturbed chromatin remodelling is the most salient factor in tumourigenesis and could thus be a potential therapeutic opportunity. Here, I review the genetic basis of aberrant chromatin remodelling in paediatric brain tumours and discuss their impact on the epigenome in the respective entities, mainly medulloblastomas and rhabdoid tumours. Aberrations described in-Rhabdoid tumours eletions/SNVs (95% of all cases) -rare entities: INI1 deficient chordomas (10-20% of all cases), CRINET (all cases) Figure 1. An overview on SWItch/sucrose non-fermentable aberrant paediatric entities. CRINET, cribriform neuroepithelial tumours. Dysregulation of chromatin remodellers in paediatric neurooncology 61 CNS CRINET Point mutations CNS CRINET, cribriform neuroepithelial tumours.

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GSK2801, a BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer

Cited by 50 publications

References 57 publications

GBAF, a small BAF sub-complex with big implications: a systematic review

GBAF, a small BAF sub-complex with big implications: a systematic review

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

Invited Review: Dysregulation of chromatin remodellers in paediatric brain tumours – SMARCB1 and beyond

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