Department of Oncology, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, 39 Jingzhou Street, Xiangyang, 441021, Hubei, People's Republic of China.
Cancer Chemother Pharmacol. 2020 Jun;85(6):1079-1087. doi: 10.1007/s00280-020-04078-0. Epub 2020 May 22.
Although substantial evidence has shown that the mammalian target of rapamycin (mTOR) pathway is an important therapeutic target in gastric cancer, the overall response rates in patients to mTOR inhibitor everolimus have been less than initially expected. We hypothesized that the limited efficacy of everolimus in gastric cancer is due to the activation of extracellular signal-regulated kinase (ERK).
ERK activation was investigated using western blot. The effects of dual inhibition of ERK and mTOR via genetic and pharmacological approaches were determined using cellular assays and xenograft mouse model.
We observed the decreased phosphorylation of mTOR, rS6, and 4EBP1 and increased phosphorylation of ERK and p90RSK in gastric cancer cells exposed to everolimus at clinically relevant concentration. Using both in vitro cell culture assays and in vivo xenograft mouse model, we found that trametinib overcame everolimus resistance by either effectively targeting resistant cells or further enhancing everolimus' efficacy in sensitive cells. Mechanism studies confirmed that trametinib overcame everolimus resistance via specifically inhibiting ERK and regulating ERK-mediated Bcl-2 family proteins in gastric cancer cells.
Inhibition of mTOR pathway can induce "paradoxical" activation of ERK in gastric cancer, and this activation can be reversed by trametinib. Since both drugs are clinically available, our findings might accelerate the initiation of clinical trials on gastric cancer using everolimus and trametinib combination.
尽管大量证据表明雷帕霉素靶蛋白（mTOR）通路是胃癌的重要治疗靶点，但 mTOR 抑制剂依维莫司在患者中的总体缓解率低于预期。我们假设依维莫司在胃癌中的疗效有限是由于细胞外信号调节激酶（ERK）的激活。
使用 Western blot 检测 ERK 的激活情况。通过遗传和药理学方法双重抑制 ERK 和 mTOR 的效果，使用细胞检测和异种移植小鼠模型进行了测定。
我们观察到在临床相关浓度的依维莫司作用下，胃癌细胞中 mTOR、rS6 和 4EBP1 的磷酸化减少，ERK 和 p90RSK 的磷酸化增加。通过体外细胞培养实验和体内异种移植小鼠模型，我们发现曲美替尼通过有效靶向耐药细胞或进一步增强依维莫司在敏感细胞中的疗效来克服依维莫司耐药性。机制研究证实，曲美替尼通过特异性抑制 ERK 并调节胃癌细胞中 ERK 介导的 Bcl-2 家族蛋白来克服依维莫司耐药性。
抑制 mTOR 通路可在胃癌中诱导“矛盾”的 ERK 激活，而这种激活可被曲美替尼逆转。由于这两种药物均已在临床上使用，我们的研究结果可能会加速使用依维莫司和曲美替尼联合治疗胃癌的临床试验的启动。
