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

Shaofang Wu, Shuzhen Wang, Siyuan Zheng, Roel Verhaak, Dimpy Koul, W. K.Alfred Yung

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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 b-catenin and regulates its nuclear translocation and transcriptional activity. The depletion of b-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 b-catenin at Ser552 . These observations suggest that MSK1/ b-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/b-catenin inhibition to induce lethal growth inhibition in human GBM.

Original languageEnglish (US)
Pages (from-to)1656-1668
Number of pages13
JournalMolecular cancer therapeutics
Volume15
Issue number7
DOIs
StatePublished - Jul 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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