MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma

Abstract

Glioblastoma multiforme (GBM) remains the deadliest malignant brain tumor, with glioma stem cells (GSCs) contributing to treatment resistance and tumor recurrence. We have identified MAPK-interacting kinases (MNKs) as potential targets for the GSC population in GBM. Isoform-level subtyping using The Cancer Genome Atlas (TCGA) revealed that both MNK genes (MKNK1 and MKNK2) are upregulated in mesenchymal GBM as compared to other subtypes. Expression of MKNK1 is associated with increased glioma grade and correlated with the mesenchymal GSC marker, CD44; and co-expression of MKNK1 and CD44 predicts poor survival in GBM. In established and patient-derived cell lines, pharmacological MNK inhibition using LY2801653 (merestinib) inhibited phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E), 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 (ELDA). When the effects of merestinib were assessed in vivo using an intracranial xenograft mouse model, improved overall survival was observed in merestinib-treated mice. Taken together, these data provide strong preclinical evidence that pharmacological MNK inhibition targets mesenchymal GBM and its GSC population. Implications These findings raise the possibility of MNK inhibition as a viable therapeutic approach to target the mesenchymal subtype of GBM.

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

“…Our study, and the work of others (38,39,48,49), strongly support the preclinical development of MNK1/2 inhibitors for the treatment of patients with melanoma, and potentially other malignancies harboring KIT aberrations.…”

“…The data described herein add melanoma to the growing list of malignancies with aberrant MNK1/2 activity (37)(38)(39)(40). This work has led to several insights into the biology of melanomas wherein KIT is mutated.…”

Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation

“…PDX cell lines were grown in serum-free Neurobasal medium (Thermo Fisher) with N-2 Supplement at a 1X final concentration (Thermo Fisher), EGF (50 ng/mL), bFGF (25 ng/mL), and penicillin/streptomycin (10 U/mL). Patient-derived MES (83Mes) and PN (AC17PN) GSC lines have been previously described (2, 21). GSCs were grown in DMEM/F12 with EGF (20 ng/mL), bFGF (20 ng/mL), heparin (5 μg/mL), B27 (2%), and gentamycin (1 mg/mL) in nonadherent flasks.…”

“…For xenograft and clinical trial samples, tumors were stained with the phospho-eIF4E (Ser209) antibody from Abcam (EP2151Y) as previously described using the BOND-MAX Automated IHC/ISH Stainer and Polymer Detection System (Leica Biosystems; ref. 21). Staining intensity was assessed by a board-certified neuropathologist (CH) who was blinded to sample identity.…”

“…In GBM, MNK signaling and mRNA translation have been implicated in resistance to the alkylating agent, temozolomide, as well as radiation (19, 20). Furthermore, we previously demonstrated that MNK activation is particularly important for the maintenance of therapy-resistant MES GSCs (21). …”