title: Novel HSP90 inhibitor NVP-HSP990 targets cell-cycle regulators to ablate Olig2-positive glioma tumor-initiating cells.
abstract: Genetic heterogeneity and signaling alterations diminish the effectiveness of single-agent therapies in glioblastoma multiforme (GBM). HSP90 is a molecular chaperone for several signaling proteins that are deregulated in glioma cells. Thus, HSP90 inhibition may offer an approach to coordinately correct multiple signaling pathways as a strategy for GBM therapy. In this study, we evaluated the effects of a novel HSP90 inhibitor, NVP-HSP990, in glioma tumor-initiating cell (GIC) populations, which are strongly implicated in the root pathobiology of GBM. In GIC cultures, NVP-HSP990 elicited a dose-dependent growth inhibition with IC50 values in the low nanomolar range. Two GIC subgroups with different responses were observed with an Olig2-expressing subset relatively more sensitive to treatment. We also showed that Olig2 is a functional marker associated with cell proliferation and response to NVP-HSP990, as NVP-HSP990 attenuated cell proliferation in Olig2-high GIC lines. In addition, NVP-HSP990 disrupted cell-cycle control mechanism by decreasing CDK2 and CDK4 and elevating apoptosis-related molecules. Mechanistic investigations revealed molecular interactions between CDK2/CDK4 and Olig2. Inhibition of CDK2/CDK4 activity disrupted Olig2-CDK2/CDK4 interactions and attenuated Olig2 protein stability. In vivo evaluation showed a relative prolongation of median survival in an intracranial model of GIC growth. Our results suggest that GBM characterized by high-expressing Olig2 GIC may exhibit greater sensitivity to NVP-HSP990 treatment, establishing a foundation for further investigation of the role of HSP90 signaling in GBM.
authors.affiliation: Brain Tumor Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Fu
authors.forename: Dimpy
authors.initials: D
authors.lastname: Koul
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Shuzhen
authors.initials: S
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Yuan
authors.forename: Howard
authors.initials: H
authors.lastname: Colman
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D005910:Glioma / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000032:analysis*; D000076104:Oligodendrocyte Transcription Factor 2; D055550:Protein Stability; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018841:HSP90 Heat-Shock Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D011728:Pyridones; D011743:Pyrimidines; C570862:2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido(4,3-d)pyrimidin-5(6H)-one; C405708:OLIG2 protein, human