MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma
Yao Zhan, … , Wilson H. Miller Jr., Sonia V. del Rincón
Yao Zhan, … , Wilson H. Miller Jr., Sonia V. del Rincón
Published October 16, 2017
Citation Information: J Clin Invest. 2017;127(11):4179-4192. https://doi.org/10.1172/JCI91258.
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Research Article Therapeutics

MNK1/2 inhibition limits oncogenicity and metastasis of KIT-mutant melanoma

Abstract

Melanoma can be stratified into unique subtypes based on distinct pathologies. The acral/mucosal melanoma subtype is characterized by aberrant and constitutive activation of the proto-oncogene receptor tyrosine kinase C-KIT, which drives tumorigenesis. Treatment of these melanoma patients with C-KIT inhibitors has proven challenging, prompting us to investigate the downstream effectors of the C-KIT receptor. We determined that C-KIT stimulates MAP kinase–interacting serine/threonine kinases 1 and 2 (MNK1/2), which phosphorylate eukaryotic translation initiation factor 4E (eIF4E) and render it oncogenic. Depletion of MNK1/2 in melanoma cells with oncogenic C-KIT inhibited cell migration and mRNA translation of the transcriptional repressor SNAI1 and the cell cycle gene CCNE1. This suggested that blocking MNK1/2 activity may inhibit tumor progression, at least in part, by blocking translation initiation of mRNAs encoding cell migration proteins. Moreover, we developed an MNK1/2 inhibitor (SEL201), and found that SEL201-treated KIT-mutant melanoma cells had lower oncogenicity and reduced metastatic ability. Clinically, tumors from melanoma patients harboring KIT mutations displayed a marked increase in MNK1 and phospho-eIF4E. Thus, our studies indicate that blocking MNK1/2 exerts potent antimelanoma effects and support blocking MNK1/2 as a potential strategy to treat patients positive for KIT mutations.

Authors

Yao Zhan, Jun Guo, William Yang, Christophe Goncalves, Tomasz Rzymski, Agnieszka Dreas, Eliza Żyłkiewicz, Maciej Mikulski, Krzysztof Brzózka, Aniela Golas, Yan Kong, Meng Ma, Fan Huang, Bonnie Huor, Qianyu Guo, Sabrina Daniela da Silva, Jose Torres, Yutian Cai, Ivan Topisirovic, Jie Su, Krikor Bijian, Moulay A. Alaoui-Jamali, Sidong Huang, Fabrice Journe, Ghanem E. Ghanem, Wilson H. Miller Jr., Sonia V. del Rincón

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Figure 6

MNK1/2 inhibitor SEL201 suppresses clonogenicity, cell migration, and in vivo tumor metastasis.

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MNK1/2 inhibitor SEL201 suppresses clonogenicity, cell migration, and in...
(A) Graph of 14-day clonogenic assay: HBL, MM61, MM111, and M230 cell lines were treated with or without 5 μM SEL201 (right). Data represent the mean ± SD, n = 3. **P < 0.01 by 2-way ANOVA. Western blot analysis of p-eIF4E and eIF4E; HBL, MM61, MM111, and M230 cell lines were treated with 5 μM SEL201 for 24 hours (left). (B) Western blot analysis of p-eIF4E and eIF4E in HBL cells following SEL201 treatment (48 hours). Cell migration was assessed by Transwell assay. Representative images are shown. Scale bars: 200 μm; original magnification, ×10. Data represent the mean ± SD, n = 3. **P < 0.01 by 1-way ANOVA. (C) HBL and MM111 cell lines were treated with 5 μM SEL201 for 24 hours (left). Western blot analysis of p-eIF4E, eIF4E, cyclin E1, and SNAIL. HBL and MM111 cell lines were treated with 5 μM SEL201 for 24 hours (right). RT-qPCR analysis for SNAI1 and CCNE1 mRNA expression. Data represent the mean ± SD, n = 3. P > 0.05 by 2-tailed Student’s t test. (D) 8 × 106 MM111 cells were injected in the tail vein of NOD/SCID mice. Tumor burden was defined as the percentage of lung area occupied by tumor cells. Representative images are shown. For the left panel, scale bars: 300 μm. For the right panel, scale bars: 50 μm. Data represent the mean ± SD, n = 10. *P < 0.05, **P < 0.01 by 2-way ANOVA. (A–C) GAPDH is used as a loading control.