Background

Bromodomain and extra-terminal (BET) proteins are epigenetic readers that bind to acetylated lysines of histones and regulate gene transcription. BET protein family members mediate the expression of various oncogenic drivers in ovarian cancer, such as the MYC and Neuregulin 1 (NRG1) genes. BRD4, the most thoroughly studied member of the BET family, is amplified in a significant subset of high-grade serous carcinomas (HGSC) of the ovary. It has been reported that BET inhibitors can attenuate the proliferation and dissemination of ovarian cancer cells by inhibiting oncogenic pathways, such as the FOXM1 and JAK/STAT pathways. BET inhibition can re-sensitize resistant ovarian cancer cells to already approved anticancer agents, including cisplatin and PARP inhibitors. This synergism was also confirmed in vivo in animal models. These and other preclinical results provide a promising basis for the application of BET inhibitors in ovarian cancer treatment. Currently, Phase I/II clinical trials explore the safety and efficacy profiles of BET inhibitors in various solid tumors, including ovarian tumors. Here, we review current knowledge on the molecular effects and preclinical activities of BET inhibitors in ovarian tumors.

Conclusions

BET proteins have emerged as new druggable targets for ovarian cancer. BET inhibitors may enhance antitumor activity when co-administered with conventional treatment regimens. Results from ongoing Phase I/II studies are anticipated to confirm this notion.

中文翻译：

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BET抑制治疗卵巢癌的临床前景

背景

Bromodomain 和额外末端 (BET) 蛋白是表观遗传阅读器，可与组蛋白的乙酰化赖氨酸结合并调节基因转录。BET 蛋白家族成员介导卵巢癌中各种致癌驱动因子的表达，例如MYC和神经调节蛋白 1 ( NRG1) 基因。BRD4 是 BET 家族中研究最彻底的成员，在卵巢的高级别浆液性癌 (HGSC) 的一个重要子集中被扩增。据报道，BET 抑制剂可以通过抑制致癌途径，如 FOXM1 和 JAK/STAT 途径来减弱卵巢癌细胞的增殖和扩散。BET 抑制可以使耐药性卵巢癌细胞对已经批准的抗癌药物（包括顺铂和 PARP 抑制剂）重新敏感。这种协同作用也在体内动物模型中得到证实。这些和其他临床前结果为 BET 抑制剂在卵巢癌治疗中的应用提供了有希望的基础。目前，I/II 期临床试验探索了 BET 抑制剂在各种实体瘤中的安全性和有效性，包括卵巢肿瘤。这里，

结论

BET 蛋白已成为卵巢癌的新药物靶点。当与常规治疗方案共同给药时，BET 抑制剂可以增强抗肿瘤活性。预计正在进行的 I/II 期研究的结果将证实这一观点。