Molecular cancer therapeutics, 2016-07, Vol.15 (7), p.1656-1668
2016
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- Autor(en) / Beteiligte
- Titel
- MSK1-Mediated β-Catenin Phosphorylation Confers Resistance to PI3K/mTOR Inhibitors in Glioblastoma
- Ist Teil von
- Molecular cancer therapeutics, 2016-07, Vol.15 (7), p.1656-1668
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2016
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-7163eISSN: 1538-8514DOI: 10.1158/1535-7163.MCT-15-0857Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4936927
- Format
- –
- Schlagworte
- Animals, Antineoplastic Agents - pharmacology, beta Catenin - metabolism, 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, Phosphatidylinositol 3-Kinases - antagonists & 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