Improving the clinical management of nasopharyngeal carcinoma (NPC) is an unmet need owing to the high incidence of treatment failure caused by radioresistance. In our study, we observed increased phosphorylation of translation initiation factor 4E (eIF4E), regulated by MAP kinase-interacting kinase (MNK), in NPC cells following irradiation treatment. Using siRNA to deplete MNK, we found that radiation-induced eIF4E phosphorylation was eliminated, NPC cell sensitivity to radiation was enhanced, and radioresistant NPC cell viability was reduced. Furthermore, we tested three pharmacological MNK inhibitors (eFT508, CGP57380, and cercosporamide) and found that they were effective against radioresistant NPC cells and synergized with irradiation. In-vivo experiments confirmed that eFT508, at a tolerable dose, inhibited the growth of radioresistant NPC and synergized with radiation in a radiosensitive NPC xenograft model. Our research highlights the activation of MNK-mediated survival mechanisms in NPC in response to radiotherapy and the potential of combining radiation with MNK inhibitors as a sensitizing strategy. Notably, eFT508 is currently being investigated in clinical trials for cancer treatment, and our findings may prompt the initiation of clinical trials using eFT508 in radioresistant NPC patients.

中文翻译：

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MNK 通路的抑制使鼻咽癌对放射治疗敏感。

由于放射抗拒引起的治疗失败率很高，因此改善鼻咽癌（NPC）的临床管理是一个未得到满足的需求。在我们的研究中，我们观察到放射治疗后鼻咽癌细胞中由 MAP 激酶相互作用激酶 (MNK) 调节的翻译起始因子 4E (eIF4E) 的磷酸化增加。使用 siRNA 消耗 MNK，我们发现辐射诱导的 eIF4E 磷酸化被消除，NPC 细胞对辐射的敏感性增强，抗辐射的 NPC 细胞活力降低。此外，我们测试了三种药理学MNK抑制剂（eFT508、CGP57380和cercosporamide），发现它们对放射抗性NPC细胞有效，并且与放射具有协同作用。体内实验证实，在可耐受剂量下，eFT508 可抑制放射抗性鼻咽癌的生长，并在放射敏感鼻咽癌异种移植模型中与放射协同作用。我们的研究强调了 NPC 响应放疗而激活 MNK 介导的生存机制，以及将放疗与 MNK 抑制剂相结合作为增敏策略的潜力。值得注意的是，eFT508 目前正在癌症治疗的临床试验中进行研究，我们的研究结果可能会促使在放射抗性鼻咽癌患者中启动使用 eFT508 的临床试验。