Abstract:
:Glioblastoma multiforme lacks effective therapy options. Although deregulated kinase pathways are drivers of malignant progression in glioblastoma multiforme, glioma cells exhibit intrinsic resistance toward 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 coexpression of proapoptotic 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 glioblastoma multiforme. Cancer Res; 76(23); 7001-11. ©2016 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Kaur A,Denisova OV,Qiao X,Jumppanen M,Peuhu E,Ahmed SU,Raheem O,Haapasalo H,Eriksson J,Chalmers AJ,Laakkonen P,Westermarck Jdoi
10.1158/0008-5472.CAN-16-1134subject
Has Abstractpub_date
2016-12-01 00:00:00pages
7001-7011issue
23eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-16-1134journal_volume
76pub_type
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