Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Oncology Department, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 201900, China.
Rutgers Cancer Institute of New Jersey, Rutgers, the State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
EBioMedicine. 2015 Nov 19;2(12):1944-56. doi: 10.1016/j.ebiom.2015.11.031. eCollection 2015 Dec.
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.
p38 MAP 激酶是一种很有前途的癌症药物靶点，但它的治疗效果尚未完全明了。在这里，我们报告称，结直肠癌（CRC）对 p38 抑制剂（p38i）的反应高度可变：虽然 p38i 诱导了一部分 CRC 的消退，但它刺激了另一部分 CRC 的生长。我们进一步表明，PP2AC 在两个不同的 CRC 亚组中差异表达，它通过在 S664、1254 和 1798 处对 TSC2 进行差异化磷酸化来决定 p38-TSC-mTORC1 信号的编程，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 至 mTORC1 信号和抗肿瘤反应。PP2AC 表达准确地预测了几种 CRC 模型中 p38i 的治疗反应，包括一大群患者来源的异种移植（PDX）。此外，我们证明了 p38 和 mTOR 激酶抑制剂的联合使用可以有效地克服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，信号转导的替代途径是导致对 p38 和 mTOR 靶向治疗反应不同的基础。本文描述的基于生物标志物的治疗策略为转移性 CRC 患者提供了一个极具吸引力的理由，这些患者由于缺乏有效的药物治疗而预后非常差。
