Cotargeting MNK and MEK kinases induces the regression of NF1-mutant cancers
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
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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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 1

eIF4E is a critical mTORC1 effector in MPNSTs.

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eIF4E is a critical mTORC1 effector in MPNSTs. (A) (Left) Immunoblots of...
(A) (Left) Immunoblots of p-ERK, 4EBP1, and p-S6 in S462 treated with 200 nM INK128 (an mTOR kinase inhibitor) and 750 nM PD901 (a MEK inhibitor) for 24 hours. (Right) Change in cell number of S462 cells treated with above concentrations of INK128 or 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). Note that –1 on the y axis corresponds to a 50% decrease in cell number. (B) Immunoblot of eIF4E (left) and fold change in cell number on days 2 and 3 relative to day 0 (right) and of S462 cells stably expressing 2 unique shRNAs against EIF4E (shEIF4E_1 and shEIF4E_2) or shCNT (mean ± SD, n = 3). (C) Number of colonies formed in soft agar by S462 cells expressing shCNT, shEIF4E_1, or shEIF4E_2 (mean ± SD, n = 4, 1-way ANOVA followed by Bonferroni’s multiple comparisons test). (D) eIF4E levels (left) and fold change in cell number after 72 hours (right) of 90-8TL cells expressing shEIF4E_1, shEIF4E_2, or shCNT (mean ± SD, n = 3, 1-way ANOVA followed by Bonferroni’s multiple comparisons test). (E) Number of soft agar colonies formed by CM173 cells (mouse MPNST) expressing shCNT or 2 independent shRNAs against Eif4e (shEif4e_3 and shEif4e_4) (mean ± SD, n = 3, 1-way ANOVA followed by Bonferroni’s multiple comparisons test). (F) Levels of eIF4E and p-ERK in S462 cells stably expressing shCNT, shEIF4E_1, or shEIF4E_2 treated with 750 nM PD901 for 24 hours. (G) Change in cell number of S462 shCNT, shEIF4E_1, or shEIF4E_2 cells treated with 750 nM PD901 or a vehicle control. Graph represents the average log2 of fold change in cell number 72 hours after treatment with PD901 relative to time 0 (mean ± SD, n = 3). Experiments were conducted at least 3 times for validation.