The limitations of targeting MEK signalling in Glioblastoma therapy

Sci Rep. 2020 May 4;10(1):7401. doi: 10.1038/s41598-020-64289-6.

Abstract

Glioblastoma (GB) is a highly aggressive, difficult to treat brain tumour. Successful treatment, consisting of maximal safe tumour de-bulking, followed by radiotherapy and treatment with the alkylating agent Temozolomide (TMZ), can extend patient survival to approximately 15 months. Combination treatments based on the inhibition of the PI3K pathway, which is the most frequently activated signalling cascade in GB, have so far only shown limited therapeutic success. Here, we use the clinically approved MEK inhibitor Trametinib to investigate its potential use in managing GB. Trametinib has a strong anti-proliferative effect on established GB cell lines, stem cell-like cells and their differentiated progeny and while it does not enhance anti-proliferative and cell death-inducing properties of the standard treatment, i.e. exposure to radiation or TMZ, neither does MEK inhibition block their effectiveness. However, upon MEK inhibition some cell populations appear to favour cell-substrate interactions in a sprouting assay and become more invasive in the Chorioallantoic Membrane assay, which assesses cell penetration into an organic membrane. While this increased invasion can be modulated by additional inhibition of the PI3K signalling cascade, there is no apparent benefit of blocking MEK compared to targeting PI3K.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis
  • Brain Neoplasms / therapy*
  • Cell Adhesion
  • Cell Death
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chorioallantoic Membrane / metabolism
  • Drug Screening Assays, Antitumor
  • Glioblastoma / therapy*
  • Humans
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation
  • Pyridones / pharmacology*
  • Pyrimidinones / pharmacology*
  • Signal Transduction
  • Temozolomide / pharmacology*
  • Translational Medical Research

Substances

  • Pyridones
  • Pyrimidinones
  • trametinib
  • MAP Kinase Kinase 1
  • Temozolomide