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Microenvironment-driven IGF-1R/PI3K signaling underlies acquired resistance to CSF1R inhibition in gliomas (CGH)

ABSTRACT: Macrophages accumulate with glioblastoma multiforme (GBM) progression, and can be acutely targeted via inhibition of colony stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. Here, we investigate whether long-term CSF-1R inhibition can stably regress GBM in preclinical trials. We show that while overall survival is significantly prolonged, tumors recur eventually in >50% of mice. Upon isolation and transplantation of recurrent tumor cells into naïve animals, gliomas re-establish sensitivity to CSF-1R inhibition, indicating that resistance is microenvironment-driven. PI3K pathway activity was elevated in recurrent GBM, driven by macrophage-derived IGF-1 and tumor cell IGF-1R. Consequently, combining IGF-1R or PI3K blockade with continuous CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. By contrast, monotherapy with IGF-1R or PI3K inhibitors in rebound or treatment-naïve tumors was less effective, indicating the necessity of combination therapy to expose PI3K signaling-dependency in recurrent disease. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors in the clinical setting.

ORGANISM(S): Mus musculus

PROVIDER: GSE80399 | GEO | 2016/05/20

SECONDARY ACCESSION(S): PRJNA318804

REPOSITORIES: GEO

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