MSK1-Mediated β-Catenin Phosphorylation Confers Resistance to PI3K/mTOR Inhibitors in Glioblastoma

Mol Cancer Ther. 2016 Jul;15(7):1656-68. doi: 10.1158/1535-7163.MCT-15-0857. Epub 2016 Apr 22.

Abstract

Glioblastoma (GBM) represents a compelling disease for kinase inhibitor therapy because most of these tumors harbor genetic alterations that result in aberrant activation of growth factor-signaling pathways. The PI3K/mammalian target of the rapamycin (mTOR) pathway is dysregulated in over 50% of human GBM but remains a challenging clinical target. Inhibitors against PI3K/mTOR mediators have limited clinical efficacy as single agents. We investigated potential bypass mechanisms to PI3K/mTOR inhibition using gene expression profiling before and after PI3K inhibitor treatment by Affymetrix microarrays. Mitogen- and stress-activated protein kinase 1 (MSK1) was markedly induced after PI3K/mTOR inhibitor treatment and disruption of MSK1 by specific shRNAs attenuated resistance to PI3K/mTOR inhibitors in glioma-initiating cells (GIC). Further investigation showed that MSK1 phosphorylates β-catenin and regulates its nuclear translocation and transcriptional activity. The depletion of β-catenin potentiated PI3K/mTOR inhibitor-induced cytotoxicity and the inhibition of MSK1 synergized with PI3K/mTOR inhibitors to extend survival in an intracranial animal model and decreased phosphorylation of β-catenin at Ser(552) These observations suggest that MSK1/β-catenin signaling serves as an escape survival signal upon PI3K/mTOR inhibition and provides a strong rationale for the combined use of PI3K/mTOR and MSK1/β-catenin inhibition to induce lethal growth inhibition in human GBM. Mol Cancer Ther; 15(7); 1656-68. ©2016 AACR.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cluster Analysis
  • Disease Models, Animal
  • Drug Resistance, Neoplasm* / genetics
  • Gene Expression
  • Gene Expression Profiling
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Humans
  • Mice
  • Models, Biological
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Xenograft Model Antitumor Assays
  • beta Catenin / metabolism*

Substances

  • Antineoplastic Agents
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • beta Catenin
  • Ribosomal Protein S6 Kinases, 90-kDa
  • TOR Serine-Threonine Kinases
  • mitogen and stress-activated protein kinase 1