Targeting of glioblastoma cell lines and glioma stem cells by combined PIM kinase and PI3K-p110α inhibition.

Asneha Iqbal,Rishi R Lulla,Leonidas C Platanias,Stewart Goldman,Shi-Yuan Cheng,Frank Eckerdt,Jonathan Bell,Francis J Giles,Ichiro Nakano

doi:10.18632/oncotarget.8899

Abstract

The PIM family of proteins encodes serine/threonine kinases with important roles in protein synthesis and cancer cell metabolism. In glioblastoma (GBM) cell lines, siRNA-mediated knockdown of PIM kinases or pharmacological inhibition of PIM kinases by SGI-1776 or AZD-1208 results in reduced phosphorylation of classic PIM effectors and also elements of the PI3K/mTOR pathway, suggesting interplay between PIM and mTOR signals in GBM cells. Combination of PIM kinase inhibitors with BYL-719, an inhibitor specific for the PI3K catalytic isoform p110α, results in enhanced antineoplastic effects in GBM cells. Additionally, pharmacologic inhibition of PIM kinases impairs growth of patient-derived glioma sphere cells, suggesting an important role for PIM kinases in cancer stem cell (CSC) function and survival. Such effects are further enhanced by concomitant inhibition of PIM kinase and p110α activities. Altogether these findings suggest that pharmacological PIM targeting in combination with PI3K inhibition may provide a unique therapeutic approach for the treatment of heterogeneous tumors containing populations of therapy-resistant CSCs in GBM.

Highlights

Glioblastoma (GBM), an aggressive heterogeneous type of high-grade glioma, is generally associated with limited clinical responses to standard therapy and poor outcome
It has been previously demonstrated that PIM kinases phosphorylate eukaryotic translation initiation factor 4B (eIF4B) and Bcl2-associated death promoter (BAD) in vitro [4], but little is known regarding the substrates for PIM kinase activity in GBM cells
LN229 cells treated with the PIM inhibitors SGI-1776 or AZD-1208 depicted a decrease in phosphorylation of eIF4B on serine 406 (Figure 1A) and BAD on serine 112 (Figure 1B), indicating that these two known PIM effectors are engaged in GBM cells

Summary

Introduction

Glioblastoma (GBM), an aggressive heterogeneous type of high-grade glioma, is generally associated with limited clinical responses to standard therapy and poor outcome. Novel therapeutic approaches are urgently needed to improve survival in patients with GBM. Proviral insertion site in Moloney murine leukemia virus (PIM) is a group of serine/threonine kinases that have established roles in the control of signals for cellular proliferation, migration, metabolism, and survival [2]. There is accumulating evidence for important roles of these kinases in survival signaling in cancer. PIM2 phosphorylates and inhibits the pro-apoptotic protein Bcl2-associated death promoter (BAD) and targets the eukaryotic translation initiation factor 4B (eIF4B) [4]. PIM kinases are expressed in the brain [2], but little is known about their potential value as therapeutic targets in brain cancer

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Conclusion