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PMID: 27199435 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Science (New York, N.Y.) ·Vol. 352 ·No. 6288 ·2016-05-20 ·Pages aad3018

Quail DF, Bowman RL, Akkari L, Quick ML, Schuhmacher AJ, Huse JT, Holland EC, Sutton JC, Joyce JA

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.

MeSH Terms
Animals Antineoplastic Combined Chemotherapy Protocols/pharmacology,therapeutic use Benzothiazoles/pharmacology,therapeutic use Drug Resistance, Neoplasm Glioblastoma/drug therapy,immunology Human Umbilical Vein Endothelial Cells Humans Imidazoles/pharmacology,therapeutic use Insulin-Like Growth Factor I/antagonists & inhibitors,metabolism Macrophages/drug effects,immunology Mice Mice, Inbred Strains NFATC Transcription Factors/metabolism Neoplasm Recurrence, Local/metabolism Neoplasms, Experimental/immunology,therapy Phosphatidylinositol 3-Kinases/metabolism Phosphoinositide-3 Kinase Inhibitors Picolinic Acids/pharmacology,therapeutic use Pyrazines/pharmacology,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
Chemicals
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
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Quail Daniela F
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
Bowman Robert L
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
Akkari Leila
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.
Quick Marsha L
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
Schuhmacher Alberto J
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA.
Huse Jason T
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Holland Eric C
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, WA 98109, USA.
Sutton James C
Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
Joyce Johanna A
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.
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.aad3018
Email
johanna@joycelab.org
Published
2016-05-20
Pages
aad3018
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC5450629
Subset
IM
Grants
NCI NIH HHS · F31 CA167863 · United States
NCI NIH HHS · P30 CA008748 · United States
Canadian Institutes of Health Research · Canada
NCI NIH HHS · R01 CA181355 · United States
NCI NIH HHS · U54 CA148967 · United States
NCI NIH HHS · F31CA167863 · United States
NCI NIH HHS · R01CA148967 · United States
Corrections
CommentIn
PMID: 27394965
External Links
PubMed source DOI: 10.1126/science.aad3018 PMC Full Text View journal details
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