Andrikopoulou Angeliki, Liontos Michalis, Koutsoukos Konstantinos, Dimopoulos Meletios-Athanasios, Zagouri Flora
Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens, 11528, Athens, Greece.
School of Medicine, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528, Athens, Greece.
Cell Oncol (Dordr). 2021 Apr;44(2):237-249. doi: 10.1007/s13402-020-00578-6. Epub 2021 Jan 19.
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.
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.
溴结构域和额外末端（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，如MYC和神经调节蛋白1（NRG1）基因。BET家族中研究最深入的成员BRD4在卵巢高级别浆液性癌（HGSC）的一个重要亚组中发生扩增。据报道，BET抑制剂可通过抑制致癌途径，如FOXM1和JAK/STAT途径，来减弱卵巢癌细胞的增殖和扩散。BET抑制可使耐药卵巢癌细胞对已获批的抗癌药物重新敏感，包括顺铂和PARP抑制剂。这种协同作用在动物模型体内也得到了证实。这些及其他临床前结果为BET抑制剂在卵巢癌治疗中的应用提供了有前景的基础。目前，I/II期临床试验正在探索BET抑制剂在包括卵巢肿瘤在内的各种实体瘤中的安全性和疗效。在此，我们综述了目前关于BET抑制剂在卵巢肿瘤中的分子效应和临床前活性的知识。
BET蛋白已成为卵巢癌新的可成药靶点。BET抑制剂与传统治疗方案联合使用时可能增强抗肿瘤活性。正在进行的I/II期研究结果有望证实这一观点。
