Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.
Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.
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DOI：
10.1038/nature16508
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发表时间：
2016-01-21
期刊：
影响因子：
64.8
通讯作者：
Polyak K
中科院分区：
文献类型：
--
作者：
Shu S;Lin CY;He HH;Witwicki RM;Tabassum DP;Roberts JM;Janiszewska M;Huh SJ;Liang Y;Ryan J;Doherty E;Mohammed H;Guo H;Stover DG;Ekram MB;Brown J;D'Santos C;Krop IE;Dillon D;McKeown M;Ott C;Qi J;Ni M;Rao PK;Duarte M;Wu SY;Chiang CM;Anders L;Young RA;Winer E;Letai A;Barry WT;Carroll JS;Long H;Brown M;Liu XS;Meyer CA;Bradner JE;Polyak K
三阴性乳腺癌(TNBC)是一种异质性和临床侵袭性疾病，目前尚无针对性的治疗方法。BET溴域抑制剂已经在几种癌症模型中显示出有效性，但尚未在TNBC中进行评估。这些抑制剂通过与其乙酰赖氨酸识别模块竞争，将BRD4等BET溴域蛋白从染色质中置换出来，导致抑制致癌转录程序。在此，我们报道了体外和体内TNBCs对BET溴域抑制的优先敏感性，为临床研究奠定了基础，并进一步推动了了解耐药机制的研究。在从先前敏感的TNBCs中选择对BET抑制产生获得性抗性的成对细胞株中，我们未能识别出门卫突变、新的驱动事件或药物泵激活。耐BET的TNBC细胞仍然依赖野生型BRD4，BRD4以不依赖溴域的方式支持转录和细胞增殖。对耐药的TNBC的蛋白质组学研究发现，与MED1和BRD4的过度磷酸化有很强的关联，这是由于PP2A的活性降低，在这里被确定为主要的BRD4丝氨酸磷酸酶。总之，这些研究提供了在TNBC中抑制BET的理论基础，并提出了基于机制的联合策略来预测临床耐药。
Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyllysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance.