Although the treatment of adult T-cell acute lymphoblastic leukemia (T-ALL) has been significantly improved, the heterogeneous genetic landscape of the disease often causes relapse. Aberrant activation of mammalian target of rapamycin (mTOR) pathway in T-ALL is responsible for treatment failure and relapse, suggesting that mTOR inhibition may represents a new therapeutic strategy. In this study, we investigated whether the mTOR complex 1 (mTORC1) inhibitor everolimus could be used as a therapeutic agent against human T-ALL. We showed that rapamycin and its analog RAD001 (everolimus) exerted only mild inhibition on the viability of Jurkat, CEM and Molt-4 cell lines (for everolimus the maximum inhibition was <40% at 100 nM), but greatly enhanced the phosphorylation of eIF4E, a downstream substrate of MAPK-interacting kinase (MNK) that was involved in promoting cell survival. Furthermore, we demonstrated in Jurkat cells that mTOR inhibitor-induced eIF4E phosphorylation was independent of insulin-like growth factor-1/insulin-like growth factor-1 receptor axis, but was secondary to mTOR inhibition. Then we examined the antileukemia effects of CGP57380, a MNK1 inhibitor, and we found that CGP57380 (4-16 μM) dose-dependently suppressed the expression of both phosphor-MNK1 and phosphor-eIF4E, thereby inhibiting downstream targets such as c-Myc and survivin in T-ALL cells. Importantly, CGP57380 produced a synergistic growth inhibitory effect with everolimus in T-ALL cells, and treatment with this targeted therapy overcame everolimus-induced eIF4E phosphorylation. In conclusion, our results suggest that dual-targeting of mTOR and MNK1/eIF4E signaling pathways may represent a novel therapeutic strategy for the treatment of human T-ALL.

中文翻译：

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MNK1抑制剂CGP57380克服了mTOR抑制剂诱导的eIF4E激活：协同杀伤人类T-ALL细胞的机制。

尽管成人T细胞急性淋巴细胞白血病（T-ALL）的治疗已得到显着改善，但该疾病的异质遗传格局常常会导致复发。T-ALL中哺乳动物靶标雷帕霉素（mTOR）途径的异常激活是治疗失败和复发的原因，这表明mTOR抑制可能代表了一种新的治疗策略。在这项研究中，我们调查了mTOR复合物1（mTORC1）抑制剂依维莫司是否可以用作抗人T-ALL的治疗剂。我们显示雷帕霉素及其类似物RAD001（依维莫司）仅对Jurkat，CEM和Molt-4细胞系的生存能力产生轻度抑制（对于依维莫司，最大抑制在100 nM时<40％），但大大增强了eIF4E的磷酸化，MAPK相互作用激酶（MNK）的下游底物，参与促进细胞存活。此外，我们在Jurkat细胞中证明了mTOR抑制剂诱导的eIF4E磷酸化独立于胰岛素样生长因子-1 /胰岛素样生长因子-1受体轴，但仅次于mTOR抑制。然后，我们检查了MNK1抑制剂CGP57380的抗白血病作用，发现CGP57380（4-16μM）剂量依赖性地抑制了磷-MNK1和磷-eIF4E的表达，从而抑制了下游靶标，例如c-Myc和T-ALL细胞中的survivin。重要的是，CGP57380与依维莫司在T-ALL细胞中产生了协同的生长抑制作用，这种靶向疗法的治疗克服了依维莫司诱导的eIF4E磷酸化。综上所述，