Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas.

Details

Ressource 1Download: 28759044_BIB_07614DBA0E81.pdf (1320.75 [Ko])
State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_07614DBA0E81
Type
Article: article from journal or magazin.
Collection
Publications
Title
Inhibition of colony stimulating factor-1 receptor abrogates microenvironment-mediated therapeutic resistance in gliomas.
Journal
Oncogene
Author(s)
Yan D., Kowal J., Akkari L., Schuhmacher A.J., Huse J.T., West B.L., Joyce J.A.
ISSN
1476-5594 (Electronic)
ISSN-L
0950-9232
Publication state
Published
Issued date
26/10/2017
Peer-reviewed
Oui
Volume
36
Number
43
Pages
6049-6058
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Glioblastomas represent the most aggressive glioma grade and are associated with a poor patient prognosis. The current standard of care, consisting of surgery, radiation and chemotherapy, only results in a median survival of 14 months, underscoring the importance of developing effective new therapeutic strategies. Among the challenges in treating glioblastomas are primary resistance and the rapid emergence of recurrent disease, which can result from tumor cell-intrinsic mechanisms in addition to tumor microenvironment (TME)-mediated extrinsic resistance. Using a PDGF-B-driven proneural glioma mouse model, we assessed a panel of tyrosine kinase inhibitors with different selectivity profiles. We found that PLX3397, an inhibitor of colony stimulating factor-1 receptor (CSF-1R), blocks glioma progression, markedly suppresses tumor cell proliferation and reduces tumor grade. By contrast, the multi-targeted tyrosine kinase inhibitors dovitinib and vatalanib, which directly target tumor cells, exert minimal anti-tumoral effects in vivo, despite killing glioma cells in vitro, suggesting a TME-mediated resistance mechanism may be involved. Interestingly, PLX3397 interferes with tumor-mediated education of macrophages and consequently restores the sensitivity of glioma cells to tyrosine kinase inhibitors in vivo in preclinical combination trials. Our findings thus demonstrate that microenvironmental alteration by CSF-1R blockade renders tumor cells more susceptible to receptor tyrosine kinase inhibition in a preclinical glioblastoma model, which may have important translational relevance.

Keywords
Aminopyridines/administration & dosage, Animals, Cell Line, Tumor, Cell Proliferation/drug effects, Disease Models, Animal, Drug Resistance, Neoplasm/genetics, Glioma/drug therapy, Glioma/genetics, Glioma/pathology, Humans, Mice, Protein Kinase Inhibitors/administration & dosage, Proto-Oncogene Proteins c-sis/genetics, Pyrroles/administration & dosage, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics, Tumor Microenvironment/drug effects
Pubmed
Web of science
Open Access
Yes
Create date
08/08/2017 11:13
Last modification date
20/08/2019 12:29
Usage data