PP2AC Level Determines Differential Programming of p38-TSC-mTOR Signaling and Therapeutic Response to p38-Targeted Therapy in Colorectal Cancer.
PP2AC Level Determines Differential Programming of p38-TSC-mTOR Signaling and Therapeutic Response to p38-Targeted Therapy in Colorectal Cancer.
复制标题
PP2AC 水平决定 p38-TSC-mTOR 信号传导的差异编程以及结直肠癌中 p38 靶向治疗的治疗反应。
DOI：
10.1016/j.ebiom.2015.11.031
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发表时间：
2015-12
期刊：
影响因子：
11.1
通讯作者：
Zheng XF
中科院分区：
文献类型：
--
作者：
Zhang Y;Wang X;Qin X;Wang X;Liu F;White E;Zheng XF
P38蛋白激酶是一种很有前景的抗癌药物靶点，但其治疗效果尚不完全清楚。在此，我们报道了结直肠癌(CRC)对p38抑制剂(P38i)的反应是高度可变的：虽然p38i诱导一个子组的CRC退化，但它刺激另一个子组的生长。我们进一步证明，PP2Ac在两个不同的CRC亚群中存在差异表达，这决定了p38-TSC-mTORC1信号的编程通过S664、1254和1798处TSC2的差异磷酸化，以及p38i的抗肿瘤活性。值得注意的是，PP2Ac水平的调节足以重新编程p38 to-mTORC1信号和抗肿瘤反应。在几种结直肠癌模型中，PP2Ac的表达可以准确地预测对p38i的治疗反应，包括大量患者来源的异种移植物(PDX)。此外，我们证明，p38和mTOR激酶抑制剂的组合有效地克服了单一药物治疗中对任何一种抑制剂的耐药性。这些结果表明，信号转导的替代路径是对p38和mTOR靶向治疗的不同反应的基础。本文描述的生物标记物引导的治疗策略为转移性结直肠癌患者的检测提供了一个令人信服的理由，这些患者由于缺乏有效的药物治疗而预后非常差。P38i在两个不同的CRC亚群中具有抗癌或促癌作用，p38-mTORC1信号的差异编程决定了治疗反应，PP2Ac表达水平程序p38-to-mTOR信号。MTOR和p38激酶抑制剂的联合使用克服了对单一药物治疗的耐药性。PP2Ac可预测一大批结直肠癌PDX模型的治疗反应。本研究探讨了一种名为p38i的发育型抗炎药物治疗结直肠癌的疗效和机制。P38i对低PP2Ac的肿瘤有明显的抑制作用，但对高PP2Ac的肿瘤有促进作用。不同的治疗结果是由于PP2Ac水平决定了p38i如何影响另一种抗癌药物靶点mTOR的活性。联合使用p38i和mTOR抑制剂可有效克服对单一药物治疗的耐药性。本研究确定PP2Ac是一种预测生物标志物和治疗策略，以指导p38靶向治疗结直肠癌患者，特别是那些带有K-Ras突变的转移性癌症患者，他们的预后非常差。
The p38 MAP kinase is a promising cancer drug target but its therapeutic effect is not fully understood. Here we report that the response of colorectal cancer (CRC) to p38 inhibitors (p38i) is highly variable: while p38i induces regression of one subgroup of CRCs, it stimulates growth of another subgroup. We further show that PP2AC is differentially expressed in the two different CRC subgroups, which determines the programing of p38-TSC-mTORC1 signaling through differential TSC2 phosphorylation at S664, 1254 and 1798, and the antitumor activity by p38i. Remarkably, modulation of PP2AC level is sufficient to reprogram p38-to-mTORC1 signaling and antitumor response. PP2AC expression accurately predicts therapeutic response to p38i in several CRC models, including a large cohort of patient-derived xenografts (PDXs). Moreover, we demonstrate that combination of p38 and mTOR kinase inhibitors effectively overcomes resistance to either inhibitor in single agent therapy. These results demonstrate that alternative routing of signal transduction underlies differential response to p38 and mTOR targeted therapies. The biomarker-guided therapeutic strategies described herein provide a compelling reason for testing in metastatic CRC patients who suffer very poor prognosis due to lack of efficacious drug therapies. p38i has anticancer or cancer-promoting effects in two distinct subgroups of CRCs Differential programing in p38-mTORC1 signaling determines therapeutic response PP2AC expression level programs p38-to-mTOR signaling. Combination of mTOR and p38 kinase inhibitors overcomes drug-resistance to single agent therapy. PP2AC predicts therapeutic response in a large cohort of CRC PDX models. This study investigates the efficacy and mechanism of a class of developmental anti-inflammatory drugs called p38i in colorectal cancer. p38i profoundly inhibits tumors with low PP2AC, but promotes tumors with high PP2AC. The different treatment outcomes are due to that PP2AC level determines how p38i affects the activity of mTOR, another cancer drug target. Combination of p38i and mTOR inhibitors effectively overcomes resistance to single agent therapies. This study identifies PP2AC as a predictive biomarker and treatment strategies to guide p38-targeted therapy for colorectal cancer patients, especially those with metastatic cancer harboring K-RAS mutations who suffer very poor prognosis.