BET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells.
BET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells.
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DOI：
10.1038/srep10120
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发表时间：
2015-05-06
影响因子：
4.6
通讯作者：
Walkley CR
中科院分区：
文献类型：
--
作者：
Baker EK;Taylor S;Gupte A;Sharp PP;Walia M;Walsh NC;Zannettino AC;Chalk AM;Burns CJ;Walkley CR
骨肉瘤(OS)的存活率停滞不前，部分原因是缺乏新的治疗选择。在这里，我们证明了溴域抑制剂(BETI)，JQ1，I-BET151，I-BET762，对原代和已建立的OS细胞株具有强大的抗肿瘤活性，其机制是通过抑制BRD4。值得注意的是，与之前在长期建立的人类OS细胞系中观察到的不同，JQ1在原代OS细胞中的抗增殖活性是由诱导凋亡而不是细胞周期停滞驱动的。相反，JQ1在OS中的活性不受MYC下调的影响。我们发现JQ1通过BRD4的置换抑制转录因子FOSL1。FOSL1的缺失表现出JQ1的抗增殖作用，证实FOSL1抑制是一种潜在的治疗OS的新方法。作为一种单一疗法，JQ1在OS移植模型中显示出显著的体内抗肿瘤活性。此外，联合治疗方法表明，JQ1增加了OS细胞对阿霉素的敏感性，并在合理结合CDK抑制剂时诱导了强大的协同活性。Beti与CDK抑制剂联合使用所获得的更高水平的活性证明了这种联合治疗的有效性。综上所述，我们的研究表明，BET抑制剂是一种很有前途的治疗OS的新方法。
Osteosarcoma (OS) survival rates have plateaued in part due to a lack of new therapeutic options. Here we demonstrate that bromodomain inhibitors (BETi), JQ1, I-BET151, I-BET762, exert potent anti-tumour activity against primary and established OS cell lines, mediated by inhibition of BRD4. Strikingly, unlike previous observations in long-term established human OS cell lines, the antiproliferative activity of JQ1 in primary OS cells was driven by the induction of apoptosis, not cell cycle arrest. In further contrast, JQ1 activity in OS was mediated independently of MYC downregulation. We identified that JQ1 suppresses the transcription factor FOSL1 by displacement of BRD4 from its locus. Loss of FOSL1 phenocopied the antiproliferative effects of JQ1, identifying FOSL1 suppression as a potential novel therapeutic approach for OS. As a monotherapy JQ1 demonstrated significant anti-tumour activity in vivo in an OS graft model. Further, combinatorial treatment approaches showed that JQ1 increased the sensitivity of OS cells to doxorubicin and induced potent synergistic activity when rationally combined with CDK inhibitors. The greater level of activity achieved with the combination of BETi with CDK inhibitors demonstrates the efficacy of this combination therapy. Taken together, our studies show that BET inhibitors are a promising new therapeutic for OS.
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选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.2
作者：
Gorlick R;Kolb EA;Houghton PJ;Morton CL;Neale G;Keir ST;Carol H;Lock R;Phelps D;Kang MH;Reynolds CP;Maris JM;Billups C;Smith MA
通讯作者：
Smith MA
DOI：
10.1158/1078-0432.ccr-12-3066
发表时间：
2013-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cheng Z;Gong Y;Ma Y;Lu K;Lu X;Pierce LA;Thompson RC;Muller S;Knapp S;Wang J
通讯作者：
Wang J
影响因子：
4.8
作者：
Jurado, Sabine;Conlan, Lindus A.;Heierhorst, Joerg
通讯作者：
Heierhorst, Joerg
影响因子：
16.6
作者：
Lamoureux, Francois;Baud'huin, Marc;Ory, Benjamin
通讯作者：
Ory, Benjamin