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

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

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Dasatinib / pharmacology*
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Melanoma / drug therapy*
  • Melanoma / enzymology
  • Melanoma / secondary
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation, Missense
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-kit / genetics
  • Signal Transduction
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Intracellular Signaling Peptides and Proteins
  • MKNK1 protein, human
  • Proto-Oncogene Proteins c-kit
  • MKNK2 protein, human
  • Protein-Serine-Threonine Kinases
  • Dasatinib

Grant support

This study also received travel grants from Québec/Wallonie-Bruxelles International for scientific exchange between Jewish General Hospital, McGill University and Institut Jules Bordet, Université Libre de Bruxelles.