Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition
Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition
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DOI：
10.18632/oncotarget.3689
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发表时间：
2015-05-20
期刊：
影响因子：
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通讯作者：
Nencioni, Alessio
中科院分区：
文献类型：
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作者：
Caffa, Irene;D'Agostino, Vito;Nencioni, Alessio
酪氨酸激酶抑制剂（TKI）现在是许多类型癌症的主要治疗方法。然而，它们的好处往往是短暂的，需要寻找安全的增强策略。禁食周期增强了临床前癌症模型中放化疗的活性，目前临床试验中正在探索基于禁食的饮食方法。禁食与 TKI 结合是否具有潜在益处仍不得而知。在这里，我们报告说，饥饿条件增加了常用 TKI 的能力，包括厄洛替尼、吉非替尼、拉帕替尼、克唑替尼和瑞格非尼，以阻止癌细胞生长，抑制丝裂原激活蛋白激酶 (MAPK) 信号通路并加强 E2F 依赖性转录抑制。在癌症异种移植模型中，TKI 和禁食周期均减缓了肿瘤生长，但组合使用时，这些干预措施比单独使用任何一种治疗方法都显着更有效。总之，禁食周期或专门设计的模拟禁食饮食应在临床研究中进行评估，作为增强临床使用中 TKI 活性的手段。
Tyrosine kinase inhibitors (TKIs) are now the mainstay of treatment in many types of cancer. However, their benefit is frequently short-lived, mandating the search for safe potentiation strategies. Cycles of fasting enhance the activity of chemo-radiotherapy in preclinical cancer models and dietary approaches based on fasting are currently explored in clinical trials. Whether combining fasting with TKIs is going to be potentially beneficial remains unknown. Here we report that starvation conditions increase the ability of commonly administered TKIs, including erlotinib, gefitinib, lapatinib, crizotinib and regorafenib, to block cancer cell growth, to inhibit the mitogen-activated protein kinase (MAPK) signaling pathway and to strengthen E2F-dependent transcription inhibition. In cancer xenografts models, both TKIs and cycles of fasting slowed tumor growth, but, when combined, these interventions were significantly more effective than either type of treatment alone. In conclusion, cycles of fasting or of specifically designed fasting-mimicking diets should be evaluated in clinical studies as a means to potentiate the activity of TKIs in clinical use.