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Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):232-7. doi: 10.1073/pnas.1422165112. Epub 2014 Dec 22.

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

Author information

1
Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115; and.
2
Harvard Medical School, Boston, MA 02115; and Medical Oncology, and Broad Institute of Harvard and MIT, Cambridge, MA 02142.
3
Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115; and Broad Institute of Harvard and MIT, Cambridge, MA 02142.
4
Departments of Cancer Biology.
5
Harvard Medical School, Boston, MA 02115; and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02115;
6
Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115; and Medical Oncology, and Broad Institute of Harvard and MIT, Cambridge, MA 02142.
7
Harvard Medical School, Boston, MA 02115; and Medical Oncology, and.
8
Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115; and david_livingston@dfci.harvard.edu.

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.

KEYWORDS:

BRD4; MYCN; in vivo screen; ovarian cancer; targeted therapy

PMID:
25535366
PMCID:
PMC4291641
DOI:
10.1073/pnas.1422165112
[Indexed for MEDLINE]
Free PMC Article
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