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

Area of Science:

• Oncology
• Immunology
• Cancer Biology

Background:

• Macrophages are crucial in glioblastoma multiforme (GBM) progression.
• Targeting colony-stimulating factor-1 receptor (CSF-1R) shows promise for GBM treatment in preclinical models.
• Mechanisms of resistance to CSF-1R inhibition in GBM remain largely unexplored.

Purpose of the Study:

• To investigate the emergence and mechanisms of resistance to CSF-1R blockade in GBM.
• To identify therapeutic strategies to overcome CSF-1R inhibitor resistance in GBM.

Main Methods:

• Utilized animal models of glioblastoma multiforme (GBM).
• Administered colony-stimulating factor-1 receptor (CSF-1R) inhibitors and assessed tumor response and recurrence.
• Analyzed molecular pathways, including phosphatidylinositol 3-kinase (PI3K) and insulin-like growth factor-1 receptor (IGF-1R) signaling, in recurrent tumors.
• Tested combination therapies involving CSF-1R inhibitors with IGF-1R or PI3K inhibitors.

Main Results:

• Sustained CSF-1R inhibition significantly prolonged survival but led to tumor recurrence in over 50% of mice.
• Tumor resistance was found to be driven by the tumor microenvironment, not intrinsic tumor cell changes.
• Recurrent GBM exhibited elevated phosphatidylinositol 3-kinase (PI3K) pathway activity, fueled by macrophage-derived insulin-like growth factor-1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R).
• Combination blockade of IGF-1R or PI3K with CSF-1R inhibition markedly improved overall survival in recurrent tumors.

Conclusions:

• Tumor microenvironment-mediated resistance to CSF-1R inhibitors is a significant challenge in GBM.
• Targeting the IGF-1/IGF-1R and PI3K pathways in conjunction with CSF-1R inhibition offers a promising therapeutic strategy for overcoming resistance in GBM.