Kinase and BET Inhibitors Together Clamp Inhibition of PI3K Signaling and Overcome Resistance to Therapy.
Kinase and BET Inhibitors Together Clamp Inhibition of PI3K Signaling and Overcome Resistance to Therapy.
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DOI：
10.1016/j.ccell.2015.05.006
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发表时间：
2015-06-08
期刊：
影响因子：
50.3
通讯作者：
Parsons R
中科院分区：
文献类型：
--
作者：
Stratikopoulos EE;Dendy M;Szabolcs M;Khaykin AJ;Lefebvre C;Zhou MM;Parsons R
不持续的酶抑制是癌症靶向治疗的障碍。在此，在由PI3K和MYC驱动的转移性乳腺癌模型中对I类PI3K抑制剂的抗性与酪氨酸激酶受体（RTK）、AKT、mTOR和MYC的反馈激活相关。布罗莫结构域和额外末端结构域（BET）蛋白的抑制剂也未能影响肿瘤生长。有趣的是，BET抑制剂降低了PI3K信号传导，并在胰岛素受体和EGFR家族RTK的调节区将BRD4与染色质解离，以减少其表达。组合的PI3K和BET抑制在广泛的肿瘤细胞系中诱导细胞死亡、肿瘤消退和PI3K信号传导的钳位抑制，以提供克服对激酶抑制剂疗法的抗性的策略。PI 3 K的抑制会诱导上游RTK的反馈激活和途径活性的快速反弹。Stratikopoulos等人表明，BRD4对于许多RTK的反馈激活是重要的，并且组合的PI3K和BET抑制维持PI3K途径抑制并增强肿瘤细胞杀伤。
Unsustained enzyme inhibition is a barrier to targeted therapy for cancer. Here, resistance to a class I PI3K inhibitor in a model of metastatic breast cancer driven by PI3K and MYC was associated with feedback activation of tyrosine kinase receptors (RTKs), AKT, mTOR, and MYC. Inhibitors of bromodomain and extra terminal domain (BET) proteins also failed to affect tumor growth. Interestingly, BET inhibitors lowered PI3K signaling and dissociated BRD4 from chromatin at regulatory regions of insulin receptor and EGFR family RTKs to reduce their expression. Combined PI3K and BET inhibition induced cell death, tumor regression, and clamped inhibition of PI3K signaling in a broad range of tumor cell lines to provide a strategy to overcome resistance to kinase inhibitor therapy. Inhibition of PI3K induces feedback activation of upstream RTKs and quick rebound of the pathway activity. Stratikopoulos et al. show that BRD4 is important for the feedback activation of many RTKs and that combined PI3K and BET inhibition sustains PI3K pathway inhibition and enhances tumor cell killing.