The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas.
Science
; 352(6288): aad3018, 2016 May 20.
Article
em En
| MEDLINE
| ID: mdl-27199435
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos Picolínicos
/
Pirazinas
/
Protocolos de Quimioterapia Combinada Antineoplásica
/
Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos
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Glioblastoma
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Resistencia a Medicamentos Antineoplásicos
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Benzotiazóis
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Microambiente Tumoral
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Imidazóis
/
Neoplasias Experimentais
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Science
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos