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首页> 外文期刊>EBioMedicine >PP2AC Level Determines Differential Programming of p38-TSC-mTOR Signaling and Therapeutic Response to p38-Targeted Therapy in Colorectal Cancer
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PP2AC Level Determines Differential Programming of p38-TSC-mTOR Signaling and Therapeutic Response to p38-Targeted Therapy in Colorectal Cancer

机译：PP2AC水平决定了p38-TSC-mTOR信号的差异编程以及对结直肠癌p38靶向疗法的治疗反应

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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.
机译：p38 MAP激酶是一种有前途的癌症药物靶标，但其疗效尚不完全清楚。在这里，我们报告说，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消退，但它刺激了另一个子组的生长。我们进一步表明，PP2AC在两个不同的CRC子组中差异表达，这决定了通过S664、1254和1798的差异TSC2磷酸化p38-TSC-mTORC1信号的编程，以及p38i的抗肿瘤活性。值得注意的是，对PP2AC水平的调节足以重新编程p38-mTORC1信号转导和抗肿瘤反应。 PP2AC的表达准确地预测了几种CRC模型（包括大量患者来源的异种移植物（PDXs））对p38i的治疗反应。此外，我们证明了p38和mTOR激酶抑制剂的组合有效克服了单药治疗中对任一抑制剂的耐药性。这些结果表明，信号转导的替代途径是对p38和mTOR靶向疗法的差异反应的基础。本文所述的生物标志物指导的治疗策略为在因缺乏有效药物疗法而预后非常差的转移性CRC患者中进行测试提供了令人信服的理由。

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