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

Kaur, A. et al. (2016) PP2A inhibitor PME-1 drives kinase inhibitor resistance in glioma cells. Cancer Research, 76(23), pp. 7001-7011. (doi: 10.1158/0008-5472.CAN-16-1134) (PMID:27671680)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ahmed, Dr Shafiq and Chalmers, Professor Anthony
• Authors: Kaur, A., Denisova, O., Qiao, X., Jumppanen, M., Peuhu, E., Ahmed, S. U., Raheem, O., Haapasalo, H. K., Eriksson, J., Chalmers, A. J., Laakkonen, P. M., and Westermarck, J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 0008-5472
• ISSN (Online): 1538-7445
• Published Online: 26 September 2016