BRD4 amplification facilitates an oncogenic gene expression program in high-grade serous ovarian cancer and confers sensitivity to BET inhibitors

Abstract

BRD4 is a transcriptional co-activator functioning to recruit regulatory complexes to acetylated chromatin. A subset of High-grade Serous Ovarian Cancer (HGSOC) patients are typified by focal, recurrent BRD4 gene amplifications. Despite previously described cancer dependencies, it is unclear whether BRD4 amplification events are oncogenic in HGSOC. We find that physiologically relevant levels of expression of BRD4 isoforms in non-transformed ovarian cells result in cellular transformation. Transcriptional profiling of BRD4-transformed ovarian cells, and BRD4-amplified HGSOC patient samples revealed shared expression patterns, including enriched MYC, and E2F1 gene signatures. Furthermore, we demonstrate that a novel BET inhibitor, AZD5153, is highly active in BRD4-amplified patient derived xenografts and uncover Neuregulin-1 as a novel BRD4 effector. Experiments involving Neuregulin-1 inhibition and exogenous addition, demonstrate Neuregulin-1 as necessary and sufficient for BRD4-mediated transformation. This study demonstrates the oncogenic potential of BRD4 amplification in cancer and establishes BRD4-amplified HGSOC as a potential patient population that could benefit from BET inhibitors.

Mutational landscape of primary, metastatic, and recurrent ovarian cancer reveals c-MYC gains as potential target for BET inhibitors

“…These preclinical data with JQ1 and GS-626510 in primary ovarian cancer cell lines and xenografts confirm and expand the results of recent in-tumor shRNA genetic screens revealing c-MYC overexpression as a therapeutic target in chemotherapy-resistant tumors through the use of BRD4 inhibitors (27,28). While previous studies have found that some ovarian tumors may contain BRD4 amplifications and that such tumors may respond to BET inhibition (29), the prevalence of these amplifications in ovarian cancer tends to be low (30). Our data did not show any significant point mutations or CNVs in any BET genes, suggesting that the activity of JQ1 and GS-626510 in our tumor models was most likely related to c-MYC amplification that may be targetable by BET inhibition along with BRD4 amplifications.…”

A cell-of-origin epigenetic tracer reveals clinically distinct subtypes of high grade serous ovarian cancer

“…Moreover, BRD4 overexpression in a OSE cell line was shown to promote tumor transformation, while inhibition of BRD4 in human HGSOC xenografts resulted in reduced tumor volume specifically in BRD4 amplified samples 36 . It will be interesting to test BRD4 inhibition in both subtypes to check whether we could highlight the BRD4 pathway as a specific target for OSE-like tumors.…”

BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages

“…The inhibitor of BET shows beneficial effects in preclinical cancer models with hematological and solid tumors, which is attributed to its selective downregulation of targeted and contextdependent gene expression (13,14). The Cancer Genome Atlas (TCGA) data illustrate that BRD4 amplification occurs most frequently in HGSOC patients across all represented cancer subtypes (15), which implies that HGSOC patients is potential demographic that will benefit from BRD4 inhibitors. Given the fact that inflammatory gene expression is tightly controlled Abbreviations: HGSOC, high-grade serous ovarian cancer; TME, tumor microenvironment; TAM, tumor-associated macrophages; CTLs, cytotoxic T lymphocytes; BET, bromodomain and extraterminal; CM, conditional medium; TFBS, transcription factor binding site.…”