Cotargeting MNK and MEK kinases induces the regression of NF1-mutant cancers
Rebecca Lock, … , Jeremy R. Graff, Karen Cichowski
Rebecca Lock, … , Jeremy R. Graff, Karen Cichowski
Published May 9, 2016
Citation Information: J Clin Invest. 2016;126(6):2181-2190. https://doi.org/10.1172/JCI85183.
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Research Article Oncology

Cotargeting MNK and MEK kinases induces the regression of NF1-mutant cancers

Abstract

Neurofibromin 1–mutant (NF1-mutant) cancers are driven by excessive Ras signaling; however, there are currently no effective therapies for these or other Ras-dependent tumors. While combined MEK and mTORC1 suppression causes regression of NF1-deficient malignancies in animal models, the potential toxicity of cotargeting these 2 major signaling pathways in humans may necessitate the identification of more refined, cancer-specific signaling nodes. Here, we have provided evidence that MAPK-interacting kinases (MNKs), which converge on the mTORC1 effector eIF4E, are therapeutic targets in NF1-deficient malignancies. Specifically, we evaluated primary human NF1-deficient peripheral nervous system tumors and found that MNKs are activated in the majority of tumors tested. Genetic and chemical suppression of MNKs in NF1-deficient murine tumor models and human cell lines potently cooperated with MEK inhibitors to kill these cancers through effects on eIF4E. We also demonstrated that MNK kinases are important and direct targets of cabozantinib. Accordingly, coadministration of cabozantinib and MEK inhibitors triggered dramatic regression in an aggressive genetically engineered tumor model. The cytotoxicity of this combination required the suppression of MNK-induced eIF4E phosphorylation and was not recapitulated by suppressing other cabozantinib targets. Collectively, these studies demonstrate that combined MNK and MEK suppression represents a promising therapeutic strategy for these incurable Ras-driven tumors and highlight the utility of developing selective MNK inhibitors for these and possibly other malignancies.

Authors

Rebecca Lock, Rachel Ingraham, Ophélia Maertens, Abigail L. Miller, Nelly Weledji, Eric Legius, Bruce M. Konicek, Sau-Chi B. Yan, Jeremy R. Graff, Karen Cichowski

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Figure 3

Multiple therapeutic agents that suppress MNK kinases cooperate with MEK inhibitors.

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Multiple therapeutic agents that suppress MNK kinases cooperate with MEK...
(A) p-eIF4E and p-ERK1/2 levels in S462 cells treated with DMSO, 10 μM CGP57380, 750 nM PD901, or both inhibitors for 24 hours. (B) Change in cell number of S462 cells treated with 10 μM CGP57380 (CGP) or 750 nM PD901 alone or in combination. Graph represents the average log2 of fold change in cell number 72 hours after treatment relative to time 0 (mean ± SD, n = 3). (C) p-eIF4E and p-ERK1/2 levels in S462 cells treated with indicated concentrations of cercosporamide (Cerco.) alone or in combination with 750 nM PD901 for 24 hours. (D) Change in cell number of S462 cells treated with 10 μM or 20 μM cercosporamide or 750 nM PD901 alone or in combination. Graph represents the average log2 of fold change in cell number 72 hours after treatment relative to time 0 (mean ± SD, n = 3). (E) Binding of tagged MNK1 and MNK2 to immobilized ligand was measured in the presence of increasing cabozantinib. Tagged MNK kinases were quantified by real-time qPCR using previously described methods (26). Representative curves are shown. (F) Levels of p-eIF4E following 24 hours of treatment with increasing concentrations of cabozantinib or 10 μM CGP57380. (G) p-eIF4E and p-ERK1/2 levels in S462 cells treated with 0.5 μM or 1 μM cabozantinib (Cabo) alone or in combination with 750 nM PD901 for 24 hours. (H) Change in cell number of S462 treated with the indicated concentrations of cabozantinib or 750 nM PD901 alone or in combination. Graph represents the average log2 of fold change in cell number 72 hours after treatment relative to time 0 (mean ± SD, n = 3). Experiments repeated at least 3 times for validation.