Mammalian target of rapamycin (mTOR) is one of the most commonly activated pathways in human cancers, including lung cancer. Targeting mTOR with molecule inhibitors is considered as a useful therapeutic strategy. However, the results obtained from the clinical trials with the inhibitors so far have not met the original expectations, largely because of the drug resistance. Thus, combined or multiple drug therapy can bring about more favorable clinical outcomes. Here, we found that activation of ERK pathway was responsible for rapamycin drug resistance in non-small-cell lung cancer (NSCLC) cells. Accordingly, rapamycin-resistant NSCLC cells were more sensitive to ERK inhibitor (ERKi), trametinib, and in turn, trametinib-resistant NSCLC cells were also susceptible to rapamycin. Combining rapamycin with trametinib led to a potent synergistic antitumor efficacy, which induced G1-phase cycle arrest and apoptosis. In addition, rapamycin synergized with another ERKi, MEK162, and in turn, trametinib synergized with other mTORi, Torin1 and OSI-027. Mechanistically, rapamycin in combination with trametinib resulted in a greater decrease of phosphorylation of AKT, ERK, mTOR and 4EBP1. In xenograft mouse model, co-administration of rapamycin and trametinib caused a substantial suppression in tumor growth without obvious drug toxicity. Overall, our study identifies a reasonable combined strategy for treatment of NSCLC.

中文翻译：

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雷帕霉素与曲美替尼：治疗NSCLC的合理组合


哺乳动物雷帕霉素靶蛋白 (mTOR) 是人类癌症（包括肺癌）中最常见的激活途径之一。用分子抑制剂靶向 mTOR 被认为是一种有用的治疗策略。然而，迄今为止，抑制剂的临床试验结果并未达到最初的预期，很大程度上是因为耐药性。因此，联合或多种药物治疗可以带来更有利的临床结果。在这里，我们发现 ERK 通路的激活是非小细胞肺癌 (NSCLC) 细胞中雷帕霉素耐药性的原因。因此，雷帕霉素耐药的 NSCLC 细胞对 ERK 抑制剂 (ERKi)、曲美替尼 (Trametinib) 更敏感，反过来，曲美替尼耐药的 NSCLC 细胞也对雷帕霉素敏感。雷帕霉素与曲美替尼联合使用可产生有效的协同抗肿瘤功效，诱导 G1 期周期停滞和细胞凋亡。此外，雷帕霉素与另一种ERKi、MEK162具​​有协同作用，而曲美替尼又与其他mTORi、Torin1和OSI-027具有协同作用。从机制上讲，雷帕霉素与曲美替尼联合使用可导致 AKT、ERK、mTOR 和 4EBP1 的磷酸化更大程度降低。在异种移植小鼠模型中，雷帕霉素和曲美替尼联合给药可显着抑制肿瘤生长，且没有明显的药物毒性。总体而言，我们的研究确定了治疗 NSCLC 的合理组合策略。