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J Clin Invest. 2017 Nov 1;127(11):4179-4192. doi: 10.1172/JCI91258. Epub 2017 Oct 16.

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

Author information

1
Experimental Medicine, Faculty of Medicine, McGill University, Montréal, Quebec, Canada.
2
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute, Beijing, China.
3
Segal Cancer Centre, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal, Quebec, Canada.
4
Selvita S.A. Kraków, Kraków, Poland.
5
Biochemistry, Goodman Cancer Center, McGill University, Montréal, Quebec, Canada.
6
Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
7
Rossy Cancer Network, McGill University, Montréal, Quebec, Canada.

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.

PMID:
29035277
PMCID:
PMC5663367
DOI:
10.1172/JCI91258
[Indexed for MEDLINE]
Free PMC Article

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