Targeting of glioblastoma cell lines and glioma stem cells by combined PIM kinase and PI3K-p110α inhibition.
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.
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division 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.
Asneha
A
Iqbal
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
Frank
F
Eckerdt
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
Jonathan
J
Bell
Department of Neurological Surgery and James Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Ichiro
I
Nakano
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
Francis J
FJ
Giles
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
Shi-Yuan
SY
Cheng
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division 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.
Rishi R
RR
Lulla
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division 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.
Stewart
S
Goldman
Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.|Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.|Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA.
Leonidas C
LC
Platanias
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines / Q000494:pharmacology*
C587575:AZD1208; D001713:Biphenyl Compounds; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C545188:SGI 1776; D013844:Thiazoles; D053778:Thiazolidines; C585539:Alpelisib; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim
PIM kinase; glioblastoma; mTOR signaling; p110α