Targeting of glioblastoma cell lines and glioma stem cells by combined PIM kinase and PI3K-p110a inhibition

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

doi:10.18632/oncotarget.8899

Targeting of glioblastoma cell lines and glioma stem cells by combined PIM kinase and PI3K-p110a inhibition

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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, siRNAmediated 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 p110a, 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 p110a 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.

Original language	English (US)
Pages (from-to)	33192-33201
Number of pages	10
Journal	Oncotarget
Volume	7
Issue number	22
DOIs	https://doi.org/10.18632/oncotarget.8899
State	Published - May 31 2016

Keywords

Glioblastoma
PIM kinase
mTOR signaling
p110a

ASJC Scopus subject areas

Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.18632/oncotarget.8899

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title = "Targeting of glioblastoma cell lines and glioma stem cells by combined PIM kinase and PI3K-p110a inhibition",

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, siRNAmediated 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 p110a, 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 p110a 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.",

keywords = "Glioblastoma, PIM kinase, mTOR signaling, p110a",

author = "Asneha Iqbal and Frank Eckerdt and Jonathan Bell and Ichiro Nakano and Giles, {Francis J.} and Cheng, {Shi Yuan} and Lulla, {Rishi R.} and Stewart Goldman and Platanias, {Leonidas C.}",

note = "Funding Information: This work was supported in part by the Hyundai Hope on Wheels Grant Program; by National Institutes of Health Grants [CA121192, CA77816] and by the Department of Veterans Affairs [I01CX000916]. JB is supported in part by a National Institutes of Health/National Cancer Institute training grant [Grant T32CA09560]. The Northwestern University's Center for Advanced Microscopy and the Flow Cytometry Facility is supported by Cancer Center Support Grant [NCI CA060553].",

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AU - Iqbal, Asneha

AU - Eckerdt, Frank

AU - Bell, Jonathan

AU - Nakano, Ichiro

AU - Giles, Francis J.

AU - Cheng, Shi Yuan

AU - Lulla, Rishi R.

AU - Goldman, Stewart

AU - Platanias, Leonidas C.

N1 - Funding Information: This work was supported in part by the Hyundai Hope on Wheels Grant Program; by National Institutes of Health Grants [CA121192, CA77816] and by the Department of Veterans Affairs [I01CX000916]. JB is supported in part by a National Institutes of Health/National Cancer Institute training grant [Grant T32CA09560]. The Northwestern University's Center for Advanced Microscopy and the Flow Cytometry Facility is supported by Cancer Center Support Grant [NCI CA060553].

PY - 2016/5/31

Y1 - 2016/5/31

N2 - The PIM family of proteins encodes serine/threonine kinases with important roles in protein synthesis and cancer cell metabolism. In glioblastoma (GBM) cell lines, siRNAmediated 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 p110a, 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 p110a 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.

AB - The PIM family of proteins encodes serine/threonine kinases with important roles in protein synthesis and cancer cell metabolism. In glioblastoma (GBM) cell lines, siRNAmediated 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 p110a, 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 p110a 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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Targeting of glioblastoma cell lines and glioma stem cells by combined PIM kinase and PI3K-p110a inhibition

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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