PP2A inhibitor PME-1 drives kinase inhibitor resistance in glioma cells

Kaur, A., Denisova, O., Qiao, X., Jumppanen, M., Peuhu, E., Ahmed, Shafiq, Raheem, O., Haapasalo, H. K., Eriksson, J., Chalmers, A. J., Laakkonen, P. M. and Westermarck, J. (2016) PP2A inhibitor PME-1 drives kinase inhibitor resistance in glioma cells. Cancer Research, 76 (23). pp. 7001-7011. ISSN 0008-5472

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Abstract

Glioblastoma multiforme (GBM) lacks effective therapy options. Although deregulated kinase pathways are drivers of malignant progression in GBM, glioma cells exhibit intrinsic resistance towards many kinase inhibitors, and the molecular basis of this resistance remains poorly understood. Here we show that overexpression of the protein phosphatase 2A (PP2A) inhibitor protein PME-1 drives resistance of glioma cells to various multikinase inhibitors. The PME-1-elicited resistance was dependent on specific PP2A complexes and was mediated by a decrease in cytoplasmic HDAC4 activity. Importantly, both PME-1 and HDAC4 associated with human glioma progression, supporting clinical relevance of the identified mechanism. Synthetic lethality induced by both PME-1 and HDAC4 inhibition was dependent on the co-expression of pro-apoptotic protein BAD. Thus, PME-1-mediated PP2A inhibition is a novel mechanistic explanation for multikinase inhibitor resistance in glioma cells. Clinically, these results may inform patient stratification strategies for future clinical trials with selected kinase inhibitors in GBM.

Item Type: Article
Subjects: Sciences > Pharmacy and Pharmacology
Divisions: Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences
Depositing User: Barry Hall
Date Deposited: 02 Nov 2016 16:27
Last Modified: 19 Feb 2020 16:02
URI: http://sure.sunderland.ac.uk/id/eprint/6784
ORCID for Shafiq Ahmed: ORCID iD orcid.org/0000-0001-8701-6889

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