Selective Killing of SMARCA2-and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models
Selective Killing of SMARCA2-and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models
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DOI：
10.1158/1535-7163.mct-16-0678
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发表时间：
2017-05-01
影响因子：
5.7
通讯作者：
Ribich, Scott A.
中科院分区：
文献类型：
--
作者：
Chan-Penebre, Elayne;Armstrong, Kelli;Ribich, Scott A.
SWI/SNF复合体是基因表达的主要调节因子，越来越多地被认为在人类癌症中发挥着重要作用，几乎所有类型的癌症都存在高频率的亚单位突变。我们以前报道过，在临床前模型中，缺乏SWI/SNF核心成分INI1(SMARCB1)的恶性横纹肌样肿瘤可以被H3K27组蛋白甲基转移酶EZH2的抑制剂选择性地杀死。鉴于SWI/SNF复合体和含有EZH2的PRC2复合体的拮抗活性，我们调查了其他具有SWI/SNF突变的癌症是否对选择性EZH2抑制敏感。最近有报道称，双缺失SWI/SNF冗余成分SMARCA4和SMARCA2的卵巢癌是一种罕见的横纹肌样亚型，称为卵巢高钙血症小细胞癌(SCCOHT)。在这里，我们提供的证据表明，一组常用的卵巢癌细胞株被误诊，而不是来自SCCOHT肿瘤。我们还证明，目前处于II期临床试验的有效和选择性的EZH2抑制剂他赛莫司坦在SCCOHT细胞株和SMARCA2和SMARCA4缺失的异种移植瘤中诱导出强大的抗增殖和抗肿瘤作用。这些结果例证了另一类依赖EZH2活性生存的横纹肌样肿瘤。(C)2017年AACR。
The SWI/SNF complex is a major regulator of gene expression and is increasingly thought to play an important role in human cancer, as evidenced by the high frequency of subunit mutations across virtually all cancer types. We previously reported that in preclinical models, malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SMARCB1), are selectively killed by inhibitors of the H3K27 histone methyltransferase EZH2. Given the demonstrated antagonistic activities of the SWI/SNF complex and the EZH2-containing PRC2 complex, we investigated whether additional cancers with SWI/SNF mutations are sensitive to selective EZH2 inhibition. It has been recently reported that ovarian cancers with dual loss of the redundant SWI/SNF componentsSMARCA4andSMARCA2are characteristic of a rare rhabdoid-like subtype known as small-cell carcinoma of the ovary hypercalcemic type (SCCOHT). Here, we provide evidence that a subset of commonly used ovarian carcinoma cell lines were misdiagnosed and instead were derived from a SCCOHT tumor. We also demonstrate that tazemetostat, a potent and selective EZH2 inhibitor currently in phase II clinical trials, induces potent antiproliferative and antitumor effects in SCCOHT cell lines and xenografts deficient in both SMARCA2 and SMARCA4. These results exemplify an additional class of rhabdoid-like tumors that are dependent on EZH2 activity for survival. (C) 2017 AACR.