Overcoming platinum resistance in preclinical models of ovarian cancer using the neddylation inhibitor MLN4924.
Overcoming platinum resistance in preclinical models of ovarian cancer using the neddylation inhibitor MLN4924.
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DOI：
10.1158/1535-7163.mct-12-1028
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发表时间：
2013-10
影响因子：
5.7
通讯作者：
Dutta A
中科院分区：
文献类型：
--
作者：
Jazaeri AA;Shibata E;Park J;Bryant JL;Conaway MR;Modesitt SC;Smith PG;Milhollen MA;Berger AJ;Dutta A
几乎无处不在的化疗耐药疾病的发展仍然是改善卵巢癌患者预后的主要障碍。在本研究中，我们评价了MLN 4924（一种NEDD 8激活酶的试验性抑制剂）在卵巢癌细胞中的临床前活性。评估了MLN 4924单独给药和与铂类联合给药的疗效。总体而言，单药MLN 4924在卵巢癌细胞系中表现出中度活性。然而，MLN 4924与顺铂或卡铂联合给药在SKOV 3和ES 2细胞以及从高级别浆液性、透明细胞和浆液性交界性卵巢肿瘤建立的原代卵巢癌细胞系中产生了协同效应。顺铂+MLN 4924的疗效在几种铂耐药卵巢癌体外模型中也很明显。从机制上讲，顺铂和MLN 4924联合给药与DNA再复制、铂-DNA加合物形成改变、FANCD 2单泛素化消除或CHK 1磷酸化无关。使用siRNA筛选研究E3泛素连接酶Cullin RING-连接酶（CRL）家族每个成员的贡献，E3泛素连接酶是MLN 4924生物学效应的最佳表征下游介质。顺铂诱导的细胞毒作用通过消耗CUL 3而增强，并且在ES 2和SKOV 3卵巢癌细胞中被siCUL 1拮抗。本研究确定Neddylation抑制是克服体外铂类耐药的一种新机制，并为铂类和MLN 4924联合治疗卵巢癌的临床研究提供了强有力的依据。
The nearly ubiquitous development of chemoresistant disease remains a major obstacle against improving outcomes for ovarian cancer patients. In this investigation we evaluated the preclinical activity of MLN4924, an investigational inhibitor of the NEDD8-activating enzyme, in ovarian cancer cells. Efficacy of MLN4924 both alone and in combination with platinum was assessed. Overall, single agent MLN4924 exhibited moderate activity in ovarian cancer cell lines. However, the combination of MLN4924 with cisplatin or carboplatin produced synergistic effects in SKOV3 and ES2 cells, as well as, in primary ovarian cancer cell lines established from high grade serous, clear cell, and serous borderline ovarian tumors. The efficacy of cisplatin plus MLN4924 was also evident in several in vitro models of platinum resistant ovarian cancer. Mechanistically, the combination of cisplatin and MLN4924 was not associated with DNA re-replication, altered platinum-DNA adduct formation, abrogation of FANCD2 monoubiquitination, or CHK1 phosphorylation. An siRNA screen was used to investigate the contribution of each member of the Cullin RING-Ligase (CRL) family of E3 ubiquitin ligases, the best characterized downstream mediators of MLN4924’s biological effects . Cisplatin-induced cytotoxicity was augmented by depletion of CUL3, and antagonized by siCUL1 in both ES2 and SKOV3 ovarian cancer cells. This investigation identifies inhibition of Neddylation as a novel mechanism for overcoming platinum resistance in vitro, and provides a strong rationale for clinical investigations of platinum and MLN4924 combinations in ovarian cancer.