Resistance to everolimus driven by epigenetic regulation of MYC in ER+ breast cancers.
Resistance to everolimus driven by epigenetic regulation of MYC in ER+ breast cancers.
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DOI：
10.18632/oncotarget.2964
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发表时间：
2015-02-10
期刊：
影响因子：
--
通讯作者：
D'Cruz CM
中科院分区：
文献类型：
--
作者：
Bihani T;Ezell SA;Ladd B;Grosskurth SE;Mazzola AM;Pietras M;Reimer C;Zinda M;Fawell S;D'Cruz CM
对PI 3 K/mTOR/Akt通路抑制剂的获得性耐药性通常与涉及癌基因激活的补偿反馈循环有关。在这里，我们已经在ER+乳腺癌细胞和模拟抗雌激素进展的长期雌激素剥夺（LTED）模型中产生了依维莫司耐药性。这使我们能够发现MYC是mTOR抑制剂耐药性的驱动因素。我们证明依维莫司耐药和依维莫司急性治疗均可导致MYC mRNA、蛋白表达上调，从而导致RNA测序数据显示的MYC特征富集。MYC的消耗导致对依维莫司的再敏感，证实了其在这种情况下的功能重要性。此外，ChIP测定表明，在依维莫司抗性系中MYC上调是由BRD 4转录因子与MYC基因的缔合增加介导的。最后，JQ 1，一种BRD 4抑制剂与依维莫司组合，在3D Matrigel模型和体内异种移植模型中表现出增加的肿瘤生长抑制。这些数据表明，MYC在ER+和ER+/LTED模型中介导对依维莫司的抗性中起重要作用。此外，考虑到在这种情况下BRD 4对MYC的调节，这些数据暗示了将表观遗传试剂与mTOR抑制剂组合以有效下调否则难以靶向的转录因子如MYC的治疗潜力增加。
Acquired resistance to PI3K/mTOR/Akt pathway inhibitors is often associated with compensatory feedback loops involving the activation of oncogenes. Here, we have generated everolimus resistance in ER+ breast cancer cells and in long-term estrogen deprived (LTED) models that mimic progression on anti-estrogens. This allowed us to uncover MYC as a driver of mTOR inhibitor resistance. We demonstrate that both everolimus resistance and acute treatment of everolimus can lead to the upregulation of MYC mRNA, protein expression and, consequently, the enrichment of MYC signatures as revealed by RNA sequencing data. Depletion of MYC resulted in resensitization to everolimus, confirming its functional importance in this setting. Furthermore, ChIP assays demonstrate that MYC upregulation in the everolimus resistant lines is mediated by increased association of the BRD4 transcription factor with the MYC gene. Finally, JQ1, a BRD4 inhibitor combined with everolimus exhibited increased tumor growth inhibition in 3D Matrigel models and an in vivo xenograft model. These data suggest that MYC plays an important role in mediating resistance to everolimus in ER+ and ER+/LTED models. Furthermore, given the regulation ofMYCby BRD4 in this setting, these data have implications for increased therapeutic potential of combining epigenetic agents with mTOR inhibitors to effectively downregulate otherwise difficult to target transcription factors such as MYC.
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影响因子：
3.5
作者：
Toh PP;Luo S;Menzies FM;Raskó T;Wanker EE;Rubinsztein DC
通讯作者：
Rubinsztein DC
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1111/nyas.12122
发表时间：
2013-01-01
期刊：
PHARMACEUTICAL SCIENCE TO IMPROVE THE HUMAN CONDITION: PRIX GALIEN USA 2012
影响因子：
--
作者：
Lebwohl, David;Anak, Oezlem;Berg, William
通讯作者：
Berg, William
影响因子：
3.8
作者：
DEMERS, LM
通讯作者：
DEMERS, LM
DOI：
10.1158/1078-0432.ccr-10-2567
发表时间：
2011-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Miller TW;Balko JM;Ghazoui Z;Dunbier A;Anderson H;Dowsett M;González-Angulo AM;Mills GB;Miller WR;Wu H;Shyr Y;Arteaga CL
通讯作者：
Arteaga CL