ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP.
ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP.
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DOI：
10.1158/0008-5472.can-16-0155
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发表时间：
2016-12-15
期刊：
影响因子：
11.2
通讯作者：
Brugge JS
中科院分区：
文献类型：
--
作者：
Muranen T;Selfors LM;Hwang J;Gallegos LL;Coloff JL;Thoreen CC;Kang SA;Sabatini DM;Mills GB;Brugge JS
PI3K/mTOR 通路的异常激活是许多癌症的共同特征，也是有吸引力的治疗靶点，但与任何癌细胞靶向治疗一样，耐药性不可避免地会发生。在动物肿瘤模型中，PI3K/mTOR 的长期抑制最初会抑制肿瘤生长，但随着时间的推移，肿瘤细胞会逃脱抑制。在这项研究中，我们发现了一种上下文依赖的逃逸机制，肿瘤细胞通过这种机制上调原癌基因转录调节因子 c-MYC 和 YAP1。该机制依赖于 ERK 的组成型活性以及应激激酶 p38 的抑制。 p38 的抑制缓解了增殖停滞，并通过稳定 CREB 上调了 MYC 和 YAP。这些数据为影响 PI3K/mTOR 抑制剂耐药性的细胞信号传导机制提供了新的见解。此外，他们表明灭活 YAP 或 MYC 或增强 p38 活性的疗法可以增强 PI3K/mTOR 抑制剂的功效。
Aberrant activation of the PI3K/mTOR-pathway is a common feature of many cancers and an attractive target for therapy, but resistance inevitably evolves is as the case for any cancer cell targeted therapy. In animal tumor models, chronic inhibition of PI3K/mTOR initially inhibits tumor growth, but over time, tumor cells escape inhibition. In this study, we identified a context-dependent mechanism of escape whereby tumor cells upregulated the proto-oncogene transcriptional regulators c-MYC and YAP1. This mechanism was dependent on both constitutive ERK activity as well as inhibition of the stress kinase p38. Inhibition of p38 relieved proliferation arrest and allowed upregulation of MYC and YAP through stabilization of CREB. These data provide new insights into cellular signaling mechanisms that influence resistance to PI3K/mTOR inhibitors. Furthermore, they suggest that therapies that inactivate YAP or MYC or augment p38 activity could enhance the efficacy of PI3K/mTOR inhibitors.