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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.

SUBMITTER: Quail DF 

PROVIDER: S-EPMC5450629 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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

Quail Daniela F DF   Bowman Robert L RL   Akkari Leila L   Quick Marsha L ML   Schuhmacher Alberto J AJ   Huse Jason T JT   Holland Eric C EC   Sutton James C JC   Joyce Johanna A JA  

Science (New York, N.Y.) 20160501 6288

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  ...[more]

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