par Zhang, Yaojun ;Guo, Jun;Yang, William;Goncalves, Christophe;Rzymski, Tomasz;Dreas, Agnieszka;Zyłkiewicz, Eliza;Mikulski, Maciej;Brzózka, Krzysztof;Golas, Aniela;Kong, Yan;Ma, Meng;Huang, Fan;Huor, Bonnie;Guo, Qianyu;Da Silva, Sabrina Daniela;Rivera-Torres, José;Cai, Yutian;Topisirovic, Ivan;Su, Jie;Bijian, Krikor;Alaoui-Jamali, Moulay Abdellah;Huang, Sidong;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
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. |