title: The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas.
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.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Daniela F
authors.initials: DF
authors.lastname: Quail
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bowman
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Department of Oncology, University of Lausanne, CH-1066, Lausanne, Switzerland. Ludwig Institute for Cancer Research, University of Lausanne, CH-1066, Lausanne, Switzerland.
authors.forename: Leila
authors.initials: L
authors.lastname: Akkari
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Quick
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Schuhmacher
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, WA 98109, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.affiliation: Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Sutton
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Department of Oncology, University of Lausanne, CH-1066, Lausanne, Switzerland. Ludwig Institute for Cancer Research, University of Lausanne, CH-1066, Lausanne, Switzerland. johanna@joycelab.org.
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Joyce
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D052160:Benzothiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005909:Glioblastoma / Q000188:drug therapy* / Q000276:immunology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D050778:NFATC Transcription Factors / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010848:Picolinic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors*; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D052160:Benzothiazoles; D007093:Imidazoles; D007334:Insulin-Like Growth Factor I; D050778:NFATC Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010848:Picolinic Acids; D011719:Pyrazines; D017526:Receptor, IGF Type 1; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D050800:STAT6 Transcription Factor; C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; C568289:4-(2-(2-hydroxycyclohexylamino)benzothiazol-6-yloxy)pyridine-2-carboxylic acid methylamide; C000604004:Csf1r protein, mouse