The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas

Science. 2016 May 20;352(6288):aad3018. doi: 10.1126/science.aad3018.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzothiazoles / pharmacology
  • Benzothiazoles / therapeutic use*
  • Drug Resistance, Neoplasm*
  • Glioblastoma / drug therapy*
  • Glioblastoma / immunology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use*
  • Insulin-Like Growth Factor I / antagonists & inhibitors
  • Insulin-Like Growth Factor I / metabolism
  • Macrophages / drug effects
  • Macrophages / immunology
  • Mice
  • Mice, Inbred Strains
  • NFATC Transcription Factors / metabolism
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasms, Experimental / immunology
  • Neoplasms, Experimental / therapy*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Picolinic Acids / pharmacology
  • Picolinic Acids / therapeutic use*
  • Pyrazines / pharmacology
  • Pyrazines / therapeutic use*
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
  • STAT6 Transcription Factor / metabolism
  • Signal Transduction
  • Tumor Microenvironment / immunology*

Substances

  • 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
  • 4-(2-(2-hydroxycyclohexylamino)benzothiazol-6-yloxy)pyridine-2-carboxylic acid methylamide
  • Benzothiazoles
  • Csf1r protein, mouse
  • Imidazoles
  • NFATC Transcription Factors
  • Phosphoinositide-3 Kinase Inhibitors
  • Picolinic Acids
  • Pyrazines
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • STAT6 Transcription Factor
  • Insulin-Like Growth Factor I
  • Receptor, IGF Type 1