An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma

Abstract

High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive form of epithelial ovarian cancer, for which few targeted therapies exist. To search for new therapeutic target proteins, we performed an in vivo shRNA screen using an established human HGSOC cell line growing either subcutaneously or intraperitoneally in immunocompromised mice. We identified genes previously implicated in ovarian cancer such as AURKA1, ERBB3, CDK2, and mTOR, as well as several novel candidates including BRD4, VRK1, and GALK2. We confirmed, using both genetic and pharmacologic approaches, that the activity of BRD4, an epigenetic transcription modulator, is necessary for proliferation/survival of both an established human ovarian cancer cell line (OVCAR8) and a subset of primary serous ovarian cancer cell strains (DFs). Among the DFs tested, the strains sensitive to BRD4 inhibition revealed elevated expression of either MYCN or c-MYC, with MYCN expression correlating closely with JQ1 sensitivity. Accordingly, primary human xenografts derived from high-MYCN or c-MYC strains exhibited sensitivity to BRD4 inhibition. These data suggest that BRD4 inhibition represents a new therapeutic approach for MYC-overexpressing HGSOCs.ovarian cancer | in vivo screen | targeted therapy | BRD4 | MYCN

Dual Targeting of Bromodomain and Extraterminal Domain Proteins, and WNT or MAPK Signaling, Inhibits c-MYC Expression and Proliferation of Colorectal Cancer Cells

“…These findings are also consistent with previous reports in multiple myeloma (6,44), acute lymphoblastic lymphoma (7), and medulloblastoma (38) cell lines where a correlation between MYC repression and growth inhibition was observed.…”

Ovarian cancer

“…Other mutated genes that play a part in the pathogenesis of HGSC and that could also serve as potential therapeutic targets for ovarian cancer include AURKA, ERBB3, CDK2, MTOR, BRD4, and MYC (63,77,78). For example, one study showed that activity of the epigenetic transcription modulator, bromodomain-containing protein 4 (encoded by BRD4) is required for the proliferation and survival of HGSC cell lines (77).…”

“…For example, one study showed that activity of the epigenetic transcription modulator, bromodomain-containing protein 4 (encoded by BRD4) is required for the proliferation and survival of HGSC cell lines (77). Also, ovarian cancer cells sensitive to BRD4 inhibition have high expression of MYC, another important gene found altered in HGSC (77).…”

Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-β–dependent mechanisms

“…In addition, high-level recruitment of BRD4 to enhancer regions has been implicated in gene-specific transcriptional activation. Evidence from a variety of approaches has implicated BET proteins, in particular BRD2 and BRD4, in a range of cancers (1,(3)(4)(5) and inhibition of BET proteins offers a novel strategy for the treatment of cancer (3,6). BET inhibitors (BETi) are small molecules that interact with the acetylated lysine binding pocket of the BET family bromodomains (6,7), interfering with BET protein binding to chromatin and consequent modulation of transcription.…”