Abstract
Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in >50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor-1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors.
Copyright © 2016, American Association for the Advancement of Science.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Benzothiazoles / pharmacology
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Benzothiazoles / therapeutic use*
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Drug Resistance, Neoplasm*
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Glioblastoma / drug therapy*
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Glioblastoma / immunology
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Human Umbilical Vein Endothelial Cells
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Humans
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Imidazoles / pharmacology
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Imidazoles / therapeutic use*
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Insulin-Like Growth Factor I / antagonists & inhibitors
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Insulin-Like Growth Factor I / metabolism
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Macrophages / drug effects
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Macrophages / immunology
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Mice
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Mice, Inbred Strains
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NFATC Transcription Factors / metabolism
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Neoplasm Recurrence, Local / metabolism
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Neoplasms, Experimental / immunology
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Neoplasms, Experimental / therapy*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Picolinic Acids / pharmacology
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Picolinic Acids / therapeutic use*
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Pyrazines / pharmacology
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Pyrazines / therapeutic use*
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Receptor, IGF Type 1 / antagonists & inhibitors
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Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
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STAT6 Transcription Factor / metabolism
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Signal Transduction
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Tumor Microenvironment / immunology*
Substances
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3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
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4-(2-(2-hydroxycyclohexylamino)benzothiazol-6-yloxy)pyridine-2-carboxylic acid methylamide
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Benzothiazoles
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Csf1r protein, mouse
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Imidazoles
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NFATC Transcription Factors
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Phosphoinositide-3 Kinase Inhibitors
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Picolinic Acids
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Pyrazines
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Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
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STAT6 Transcription Factor
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Insulin-Like Growth Factor I
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Receptor, IGF Type 1