Combined inhibition of BET bromodomain and mTORC1/2 provides therapeutic advantage for rhabdomyosarcoma by switching cell death mechanism.
Combined inhibition of BET bromodomain and mTORC1/2 provides therapeutic advantage for rhabdomyosarcoma by switching cell death mechanism.
复制标题
DOI：
10.1002/mc.23414
复制
发表时间：
2022-08
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
多种复杂信号通路的异常激活是横纹肌肉瘤（RMS）发病机制的基础，RMS仍然是约30% RMS儿童死亡的原因。溴结构域和末端外（BET）结构域染色质重塑调节这些途径中的几个。在这里，我们靶向布罗莫结构域4（BRD 4）与另一种分子代谢肿瘤驱动因子Akt/mTOR信号通路组合，为这种肿瘤提供高效治疗。我们证明了这两种分子途径的联系是RMS发病机制的基础。我们的数据显示BET布罗莫结构域和mTORC 1/2信号传导的组合抑制消除了侵袭性RMS生长。因此，布罗莫结构域抑制剂RVX-208在体外和在人异种移植鼠模型中显著增强双重mTORC 1/2抑制剂OSI-027和PP 242的治疗效果。药物治疗的残留肿瘤显示出潜在信号传导机制的激活减少，其特征在于p-AKT、p-mTOR、p-p70 S6 K、细胞周期蛋白D1和增殖的表达减少。我们的ChIP-seq数据表明，RVX-208有效地阻断了BRD 4对其靶基因启动子的占据。ChIP-qPCR测定进一步证实，RVX-208处理导致其靶基因座处的H3 K27 ac和H4 K8 ac信号的显著降低。虽然单用RVX-208处理诱导细胞凋亡，单用mTORC 1/2抑制剂诱导巨胞饮，但它们的联合处理导致坏死性凋亡介导的细胞死亡。这些数据表明，靶向BRD 4和mTORC 1/2的药物联合治疗可能是耐药RMS的有效治疗干预。
Aberrant activation of multiple complex signaling pathways underlies the pathogenesis of rhabdomyosarcoma (RMS), which remains a cause of mortality in approximately 30% of children with RMS. Bromodomain and extraterminal (BET) domain chromatin remodeling regulates several of these pathways. Here, we targeted bromodomain 4 (BRD4) in combination with another molecular metabolic tumor driver, the Akt/mTOR signaling pathway, to provide a highly effective treatment for this neoplasm. We demonstrated that a nexus of these two molecular pathways underlies RMS pathogenesis. Our data show that the combined inhibition of the BET bromodomain and mTORC1/2 signaling abrogates aggressive RMS growth. Thus, the bromodomain inhibitor RVX-208 significantly augmented the therapeutic effects of the dual mTORC1/2 inhibitors, OSI-027 and PP242, both in vitro and in a human xenograft murine model. Drug-treated residual tumors showed a decrease in the activation of underlying signaling mechanisms characterized by a reduction in the expression of p-AKT, p-mTOR, p-p70S6K, cyclin D1, and proliferation. Our ChIP-seq data demonstrated that RVX-208 effectively blocked BRD4 occupancy of its target gene promoters. ChIP-qPCR assays further confirmed that RVX-208 treatment resulted in a significant decrease in H3K27ac and H4K8ac signals at their target loci. While single RVX-208 treatment induces apoptosis and a single mTORC1/2 inhibitor induces macropinocytosis, their combined treatment led to necroptosis-mediated cell death. These data suggest that combined treatment with drugs targeting BRD4 and mTORC1/2 may be an effective therapeutic intervention for drug-resistant RMS.
登录
查看更多内容
影响因子：
6.2
作者：
Ognjanovic, Simona;Linabery, Amy M.;Charbonneau, Bridget;Ross, Julie A.
通讯作者：
Ross, Julie A.
影响因子：
5.7
作者：
Garcia PL;Miller AL;Gamblin TL;Council LN;Christein JD;Arnoletti JP;Heslin MJ;Reddy S;Richardson JH;Cui X;van Waardenburg RCAM;Bradner JE;Yang ES;Yoon KJ
通讯作者：
Yoon KJ
RIP3 的裂解通过去除激酶结构域使其不依赖 caspase 的细胞凋亡途径失活
影响因子：
4.8
作者：
Feng, Shanshan;Yang, Yonghui;Wu, Mian
通讯作者：
Wu, Mian
影响因子：
64.8
作者：
Faivre, Emily J.;McDaniel, Keith F.;Shen, Yu
通讯作者：
Shen, Yu
影响因子：
45.3
作者：
Oberlin, Odile;Rey, Annie;Anderson, James R.
通讯作者：
Anderson, James R.