par Zhang, Yaojun ; Guo, Jun J.; Yang, William W.; Goncalves, Christophe C.; Rzymski, Tomasz T.; Dreas, Agnieszka A.; Zyłkiewicz, Eliza E.; Mikulski, Maciej M.; Brzózka, Krzysztof K.; Golas, Aniela A.; Kong, Yan Y.; Ma, Meng M.; Huang, Fan F.; Huor, Bonnie B.; Guo, Qianyu Q.; Da Silva, Sabrina Daniela S.D.; Rivera-Torres, José J; Cai, Yutian Y.; Topisirovic, Ivan I.; Su, Jie J.; Bijian, Krikor K.; Alaoui-Jamali, Moulay Abdellah M.A.; Huang, Sidong S.; Journé, Fabrice ; Ghanem, Ghanem Elias ; Miller, Wilson W.H.; Del Rincón, Sonia S.V.
Référence The Journal of clinical investigation, 127, 11, (page 4179-4192)
Publication Publié, 2017-11
Article révisé par les pairs
|Résumé :||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.|