MNK inhibition disrupts mesenchymal glioma stem cells and prolongs survival in a mouse model of glioblastoma

Jonathan B. Bell, Frank D. Eckerdt, Kristen Alley, Lisa P. Magnusson, Hridi Hussain, Yingtao Bi, Ahmet Dirim Arslan, Jessica Clymer, Angel A. Alvarez, Stewart Goldman, Shi Yuan Cheng, Ichiro Nakano, Craig Horbinski, Ramana V. Davuluri, C. David James, Leonidas C. Platanias*

*Corresponding author for this work

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Glioblastoma multiforme remains the deadliest malignant brain tumor, with glioma stem cells (GSC) contributing to treatment resistance and tumor recurrence. We have identified MAPKinteracting kinases (MNK) as potential targets for the GSC population in glioblastoma multiforme. Isoform-level subtyping using The Cancer Genome Atlas revealed that both MNK genes (MKNK1 and MKNK2) are upregulated in mesenchymal glioblastoma multiforme as compared with other subtypes. Expression of MKNK1 is associated with increased glioma grade and correlated with the mesenchymal GSC marker, CD44, and coexpression of MKNK1 and CD44 predicts poor survival in glioblastoma multiforme. In established and patient-derived cell lines, pharmacologic MNK inhibition using LY2801653 (merestinib) inhibited phosphorylation of the eukaryotic translation initiation factor 4E, a crucial effector for MNK-induced mRNA translation in cancer cells and a marker of transformation. Importantly, merestinib inhibited growth of GSCs grown as neurospheres as determined by extreme limiting dilution analysis. When the effects of merestinib were assessed in vivo using an intracranial xenograft mouse model, improved overall survival was observed in merestinibtreated mice. Taken together, these data provide strong preclinical evidence that pharmacologic MNK inhibition targets mesenchymal glioblastoma multiforme and its GSC population. Implications: These findings raise the possibility of MNK inhibition as a viable therapeutic approach to target the mesenchymal subtype of glioblastoma multiforme.

Original languageEnglish (US)
Pages (from-to)984-993
Number of pages10
JournalMolecular Cancer Research
Volume14
Issue number10
DOIs
StatePublished - Oct 1 2016

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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