An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma
An in-tumor genetic screen reveals that the BET bromodomain protein, BRD4, is a potential therapeutic target in ovarian carcinoma
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DOI：
10.1073/pnas.1422165112
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发表时间：
2015-01-06
影响因子：
11.1
通讯作者：
Livingston, David M.
中科院分区：
文献类型：
--
作者：
Baratta, Maria Giuseppina;Schinzel, Anna C.;Livingston, David M.
高级别浆液性卵巢癌（HGSOC）是上皮性卵巢癌中最常见和最具侵袭性的形式，目前几乎没有靶向治疗方法。为了寻找新的治疗靶蛋白，我们使用在免疫受损小鼠中皮下或腹膜内生长的已建立的人HGSOC细胞系进行了体内shRNA筛选。我们鉴定了以前与卵巢癌有关的基因，如AURKA 1，ERBB 3，CDK 2和mTOR，以及几个新的候选基因，包括BRD 4，VRK 1和GALK 2。我们使用遗传学和药理学方法证实，BRD 4（一种表观遗传转录调节剂）的活性对于已建立的人卵巢癌细胞系（OVCAR 8）和原发性浆液性卵巢癌细胞株（DF）的子集的增殖/存活是必需的。在测试的DF中，对BRD 4抑制敏感的菌株显示MYCN或c-MYC的表达升高，MYCN表达与JQ 1敏感性密切相关。因此，源自高MYCN或c-MYC菌株的原代人类异种移植物对BRD 4抑制表现出敏感性。这些数据表明，BRD 4抑制代表了MYC过表达HGSOC的新治疗方法。
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.