ABSTRACT

(1) Background: BET bromodomain proteins regulate transcription by binding acetylated histones and attracting key factors for, e.g., transcriptional elongation. BET inhibitors have been developed to block pathogenic processes such as cancer and inflammation. Despite having potent biological activities, BET inhibitors have still not made a breakthrough in clinical use for treating cancer. Multiple resistance mechanisms have been proposed but thus far no attempts to block this in glioma has been made. (2) Methods: Here, we have conducted a pharmacological synergy screen in glioma cells to search for possible combination treatments augmenting the apoptotic response to BET inhibitors. We first used HMBA, a compound that was developed as a differentiation therapy four decades ago but more recently was shown to primarily inhibit BET bromodomain proteins. Data was also generated using other BET inhibitors. (3) Results: In the synergy screen, we discovered that several MEK inhibitors can enhance apoptosis in response to HMBA in rat and human glioma cells in vitro as well as in vivo xenografts. The combination is not unique to HMBA but also other BET inhibitors such as JQ1 and I-BET-762 can synergize with MEK inhibitors. (4) Conclusions: Our findings validate a combination therapy previously demonstrated to exhibit anti-cancer activities in multiple other tumour types but which appears to have been lost in translation to the clinic.

摘要

(1) 背景：BET 溴结构域蛋白通过结合乙酰化组蛋白和吸引关键因素（例如转录延伸）来调节转录。BET 抑制剂已被开发用于阻断癌症和炎症等致病过程。尽管具有强大的生物活性，但 BET 抑制剂在临床用于治疗癌症方面仍未取得突破。已经提出了多种耐药机制，但迄今为止还没有尝试在神经胶质瘤中阻止这种机制。(2) 方法：在这里，我们在神经胶质瘤细胞中进行了药理学协同筛选，以寻找可能的联合治疗来增强对 BET 抑制剂的细胞凋亡反应。我们首先使用 HMBA，这是一种在 40 年前作为分化疗法开发的化合物，但最近显示主要抑制 BET 溴结构域蛋白。还使用其他 BET 抑制剂生成数​​据。(3) 结果：在协同筛选中，我们发现几种 MEK 抑制剂可以在体外和体内异种移植物中增强大鼠和人神经胶质瘤细胞对 HMBA 的凋亡反应。这种组合不是 HMBA 独有的，其他 BET 抑制剂如 JQ1 和 I-BET-762 也可以与 MEK 抑制剂协同作用。(4) 结论：我们的研究结果验证了先前证明在多种其他肿瘤类型中表现出抗癌活性的联合疗法，但在临床转化中似乎已经丢失了。这种组合不是 HMBA 独有的，其他 BET 抑制剂如 JQ1 和 I-BET-762 也可以与 MEK 抑制剂协同作用。(4) 结论：我们的研究结果证实了先前证明在多种其他肿瘤类型中表现出抗癌活性的联合疗法，但这种联合疗法似乎在转化为临床时已丢失。这种组合不是 HMBA 独有的，其他 BET 抑制剂如 JQ1 和 I-BET-762 也可以与 MEK 抑制剂协同作用。(4) 结论：我们的研究结果证实了先前证明在多种其他肿瘤类型中表现出抗癌活性的联合疗法，但这种联合疗法似乎在转化为临床时已丢失。