The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas Journal Article
| Authors: | Quail, D. F.; Bowman, R. L.; Akkari, L.; Quick, M. L.; Schuhmacher, A. J.; Huse, J. T.; Holland, E. C.; Sutton, J. C.; Joyce, J. A. |
| Article 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 highgrade 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. |
| Journal Title: | Science |
| Volume: | 352 |
| Issue: | 6288 |
| ISSN: | 0036-8075 |
| Publisher: | American Association for the Advancement of Science |
| Date Published: | 2016-05-20 |
| Start Page: | aad3018 |
| Language: | English |
| DOI: | 10.1126/science.aad3018 |
| PROVIDER: | scopus |
| PUBMED: | 27199435 |
| PMCID: | PMC5450629 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 July 2016 -- Source: Scopus |
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