Baratta Maria Giuseppina, Schinzel Anna C, Zwang Yaara, Bandopadhayay Pratiti, Bowman-Colin Christian, Kutt Jennifer, Curtis Jennifer, Piao Huiying, Wong Laura C, Kung Andrew L, Beroukhim Rameen, Bradner James E, Drapkin Ronny, Hahn William C, Liu Joyce F, Livingston David M
Departments of Cancer Biology, Harvard Medical School, Boston, MA 02115; and.
Harvard Medical School, Boston, MA 02115; and Medical Oncology, and Broad Institute of Harvard and MIT, Cambridge, MA 02142.
Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):232-7. doi: 10.1073/pnas.1422165112. Epub 2014 Dec 22.
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.
高级别浆液性卵巢癌（HGSOC）是上皮性卵巢癌最常见且侵袭性最强的形式，针对其的靶向治疗方法很少。为了寻找新的治疗靶点蛋白，我们使用一种已建立的人类HGSOC细胞系在免疫缺陷小鼠皮下或腹腔内生长，进行了体内短发夹RNA（shRNA）筛选。我们鉴定出了先前与卵巢癌相关的基因，如极光激酶A1（AURKA1）、表皮生长因子受体3（ERBB3）、细胞周期蛋白依赖性激酶2（CDK2）和雷帕霉素靶蛋白（mTOR），以及几个新的候选基因，包括溴结构域蛋白4（BRD4）、酪蛋白激酶VRK1（VRK1）和半乳糖激酶2（GALK2）。我们使用基因和药理学方法证实，表观遗传转录调节因子BRD4的活性对于已建立的人类卵巢癌细胞系（OVCAR8）和一部分原发性浆液性卵巢癌细胞株（DFs）的增殖/存活是必需的。在测试的DFs中，对BRD4抑制敏感的细胞株显示MYCN或c-MYC的表达升高，其中MYCN的表达与JQ1敏感性密切相关。因此，源自高MYCN或c-MYC细胞株的原发性人异种移植物对BRD4抑制表现出敏感性。这些数据表明，抑制BRD4代表了一种针对MYC过表达的HGSOC的新治疗方法。
