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

Authors: Xian-bo Huang1, Chun-mei Yang1,2, Qing-mei Han1, Xiu-jin Ye1, Wen Lei1,2,3, Wen-bin Qian1,2,3
1 Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
2 Malignant Lymphoma Diagnosis and Therapy Center, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
3 Institute of Hematology, Zhejiang University, Hangzhou 310003, China
Correspondence to: Xiu-jin Ye: yxjsunny@163.com, Wen-bin Qian: qianwb@zju.edu.cn,
DOI: 10.1038/s41401-018-0161-0
Received: 9 April 2018
Accepted: 30 July 2018
Advance online: 8 October 2018

Abstract

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.
Keywords: T-ALL; mTOR; MNK1; eIF4E; drug-resistance; everolimus; CGP57380

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