BRD4 Levels Determine the Response of Human Lung Cancer Cells to BET Degraders That Potently Induce Apoptosis through Suppression of Mcl-1
BRD4 Levels Determine the Response of Human Lung Cancer Cells to BET Degraders That Potently Induce Apoptosis through Suppression of Mcl-1
复制标题
BRD4 水平决定人肺癌细胞对 BET 降解剂的反应，BET 降解剂通过抑制 Mcl-1 有效诱导细胞凋亡
DOI：
10.1158/0008-5472.can-19-3674
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发表时间：
2020-06-01
期刊：
影响因子：
11.2
通讯作者：
Sun, Shi-Yong
中科院分区：
文献类型：
--
作者：
Zong, Dan;Gu, Jiajia;Sun, Shi-Yong
肺癌约占80%的非小细胞肺癌(NSCLC)和20%的小细胞肺癌(SCLC)，尽管在早期诊断、靶向治疗和免疫治疗方面取得了进展，但仍是全球癌症相关死亡的主要原因。因此，仍然迫切需要新的治疗方法。溴结构域和端外(BET)蛋白主要由BRD2、BRD3和BRD4蛋白组成，是表观遗传阅读器和主要转录辅助激活因子，现在被公认为癌症治疗的靶点。BET降解剂如ZBC260和DBET代表了一类通过诱导BET降解起作用的新型BET抑制剂。目前的研究证明了BET降解物，特别是ZBC260，对肺癌的治疗效果，以及了解潜在的机制和确定决定细胞对BET降解物敏感性的分子标志物。一组NSCLC细胞对ZBC260和DBET的反应模式相似，但对BET抑制剂JQ-1的反应不同。BRD水平，特别是BRD4，与对BET降解剂的高敏感性呈正相关，但与JQ-1无关。BET降解物能有效地诱导敏感的非小细胞肺癌细胞凋亡，并伴随着Mcl-1和c-flip水平的降低，这在介导诱导细胞凋亡和增强TRAIL诱导的细胞凋亡中起关键作用。因此，ZBC260在体内比JQ-1具有更强的抑制NSCLC和患者来源的异种移植瘤生长的活性。这些发现保证了未来BET降解物在非小细胞肺癌中的有效性的临床验证，特别是那些BRD蛋白水平高的患者，特别是BRD4。意义：目前的研究证明了新型BET降解物在肺癌治疗中的潜力，并保证了BET降解物在BRD4水平高的肺癌中的临床验证。
Lung cancer consists of approximately 80% non-small cell lung cancer (NSCLC) and 20% small cell lung cancer (SCLC) and remains the leading cause of cancer-related deaths worldwide despite advances in early diagnosis, targeted therapy, and immunotherapy. Thus, novel therapies are still urgently needed. Bromodomain and extraterminal (BET) proteins, primarily comprised of BRD2, BRD3, and BRD4 proteins, function as epigenetic readers and master transcription coactivators and are now recognized cancer therapeutic targets. BET degraders such as ZBC260 and dBET represent a novel class of BET inhibitors that act by inducing BET degradation. The current study demonstrates the therapeutic efficacies of BET degraders, particularly ZBC260, against lung cancer, as well as understanding the underlying mechanisms and identifying molecular markers that determine cell sensitivity to BET degraders. A panel of NSCLC cell lines possessed similar response patterns to ZBC260 and dBET but different responses to BET inhibitor JQ-1. BRD levels, particularly BRD4, correlated positively with high sensitivity to BET degraders but not to JQ-1. BET degraders potently induced apoptosis in sensitive NSCLC cells and were accompanied by reduction of Mcl-1 and c-FLIP levels, which are critical for mediating induction of apoptosis and enhancement of TRAIL-induced apoptosis. Accordingly, ZBC260 exerted more potent activity than JQ-1 in vivo against the growth of NSCLC xenografts and patient-derived xenografts. These findings warrant future clinical validation of the efficacy of BET degraders in NSCLC, particularly those with high levels of BRD proteins, especially BRD4.Significance: The current study demonstrates the potential of novel BET degraders in the treatment of lung cancer and warrants clinical validation of BET degraders in lung cancer with high levels of BRD4.