MNK1 inhibitor CGP57380 overcomes mTOR inhibitor-induced activation of eIF4E: the mechanism of synergic killing of human T-ALL cells

• 来源期刊: 中国药理学报（英文版）
• 关键词: T-ALL mTOR MNK1 eIF4E drug-resistance everolimus CGP57380
• 年，卷（期）: 2018,（12）
• 页码范围: 1894-1901
• 页数: 8页
• 语种: 英文

摘要

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 TALL 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.