Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4264, USA.
Carcinogenesis. 2010 Jul;31(7):1284-91. doi: 10.1093/carcin/bgq059. Epub 2010 Mar 18.
Selective drugs targeting dysregulated oncogenic pathways are promising cancer therapies. Because the mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in human follicular thyroid cancer (FTC), we hypothesized that its inhibition could block cancer development and progression. We, therefore, analyzed the effect of a treatment with a specific mTORC1 inhibitor (RAD001) in a faithful mouse model of FTC with constitutive mTORC1 activation (TRbeta(PV/PV)Pten(+/-) mice). The treatment did not prevent capsular and vascular invasion of the thyroid and the occurrence of lung metastasis. However, it substantially decelerated thyroid tumor growth, thereby prolonging TRbeta(PV/PV)Pten(+/-) mouse life span. RAD001 efficiently inhibited mTORC1 activity, as shown by the reduced phosphorylation of its downstream targets involved in the activity of the translation machinery, such as ribosomal S6 kinase (p70(S6K)), eukaryotic translation initiation factor 4E binding protein (4E-BP1) and the eukaryotic translation initiation factors eIF-4B and eIF-4G. Whereas mTORC1 signaling inhibition did not alter cell apoptosis, it induced a significant decrease in cell proliferation that was associated with the reduced abundance and altered activity of key regulators of cell cycle progression. Altogether, our data indicate that mTORC1 signaling plays a major role in the integration of the mitogenic signal in FTC. Therefore, our preclinical study with a relevant mouse model of FTC demonstrates for the first time that RAD001 efficaciously stabilizes cancer growth although it does not prevent its fatal outcome. In conclusion, our work underscores that in the treatment of FTC patients, RAD001 can only be used in combination with drugs and therapies inducing tumor shrinkage and blocking metastasis.
选择性靶向失调致癌途径的药物是很有前途的癌症治疗方法。由于哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）途径在人类滤泡性甲状腺癌（FTC）中过度激活，我们假设其抑制作用可以阻断癌症的发展和进展。因此，我们分析了在具有组成性 mTORC1 激活的 FTC 的忠实小鼠模型（TRβ（PV/PV）Pten（+/-）小鼠）中用特定的 mTORC1 抑制剂（RAD001）治疗的效果。该治疗并未阻止甲状腺的包膜和血管浸润以及肺转移的发生。然而，它大大减缓了甲状腺肿瘤的生长，从而延长了 TRβ（PV/PV）Pten（+/-）小鼠的寿命。RAD001 有效地抑制了 mTORC1 活性，这表现为其下游参与翻译机制活性的靶标如核糖体 S6 激酶（p70（S6K））、真核翻译起始因子 4E 结合蛋白（4E-BP1）和真核翻译起始因子 eIF-4B 和 eIF-4G 的磷酸化减少。虽然 mTORC1 信号抑制没有改变细胞凋亡，但它诱导了细胞增殖的显著减少，这与细胞周期进程关键调节剂的丰度和活性改变有关。总的来说，我们的数据表明 mTORC1 信号在 FTC 中整合有丝分裂信号中起主要作用。因此，我们使用相关的 FTC 小鼠模型进行的临床前研究首次表明，RAD001 虽然不能预防其致命结局，但能有效地稳定癌症的生长。总之，我们的工作强调了在 FTC 患者的治疗中，RAD001 只能与诱导肿瘤缩小和阻断转移的药物和疗法联合使用。
