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 journalArticle

10 Citations (Scopus)

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 1 2016
Externally publishedYes

Fingerprint

Catenins
Sirolimus
Glioblastoma
Phosphatidylinositol 3-Kinases
Phosphorylation
mitogen and stress-activated protein kinase 1
Survival
Gene Expression Profiling
Glioma
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Animal Models

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

MSK1-Mediated βb-Catenin Phosphorylation Confers Resistance to PI3K/mTOR Inhibitors in Glioblastoma. / Wu, Shaofang; Wang, Shuzhen; Zheng, Siyuan; Verhaak, Roel; Koul, Dimpy; Yung, W. K.Alfred.

In: Molecular Cancer Therapeutics, Vol. 15, No. 7, 01.07.2016, p. 1656-1668.

Research output: Contribution to journalArticle

Wu, Shaofang ; Wang, Shuzhen ; Zheng, Siyuan ; Verhaak, Roel ; Koul, Dimpy ; Yung, W. K.Alfred. / MSK1-Mediated βb-Catenin Phosphorylation Confers Resistance to PI3K/mTOR Inhibitors in Glioblastoma. In: Molecular Cancer Therapeutics. 2016 ; Vol. 15, No. 7. pp. 1656-1668.
@article{ba468b21b2964a5cb9bac4222b1a63cd,
title = "MSK1-Mediated βb-Catenin Phosphorylation Confers Resistance to PI3K/mTOR Inhibitors in Glioblastoma",
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.",
author = "Shaofang Wu and Shuzhen Wang and Siyuan Zheng and Roel Verhaak and Dimpy Koul and Yung, {W. K.Alfred}",
year = "2016",
month = "7",
day = "1",
doi = "10.1158/1535-7163.MCT-15-0857",
language = "English (US)",
volume = "15",
pages = "1656--1668",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - MSK1-Mediated βb-Catenin Phosphorylation Confers Resistance to PI3K/mTOR Inhibitors in Glioblastoma

AU - Wu, Shaofang

AU - Wang, Shuzhen

AU - Zheng, Siyuan

AU - Verhaak, Roel

AU - Koul, Dimpy

AU - Yung, W. K.Alfred

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84979547112&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84979547112&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-15-0857

DO - 10.1158/1535-7163.MCT-15-0857

M3 - Article

C2 - 27196759

AN - SCOPUS:84979547112

VL - 15

SP - 1656

EP - 1668

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 7

ER -