Targeting of glioblastoma cell lines and glioma stem cells by combined PIM kinase and PI3K-p110α inhibition
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Asneha Iqbal1,2, Frank Eckerdt1, Jonathan Bell1,3, Ichiro Nakano4, Francis J. Giles1,3, Shi-Yuan Cheng1, Rishi R. Lulla1,2, Stewart Goldman1,2, Leonidas C. Platanias1,3,5
1Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
2Division of Hematology/Oncology/Stem Cell Transplantation, Ann and Robert H. Lurie Children’s Hospital of Chicago, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
3Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
4Department of Neurological Surgery and James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
5Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA
Leonidas C. Platanias, e-mail: [email protected]
Keywords: glioblastoma, PIM kinase, mTOR signaling, p110α
Received: February 04, 2016 Accepted: April 05, 2016 Published: April 21, 2016
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.
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