Effect of MK-8931 on GSC gene expression

Glioblastoma (GBM), contains different tumor-associated macrophage (TAM) populations that can either promote tumor growth and therapeutic resistance (pTAMs) or have tumor suppressive properties (sTAMs), and thus reprograming pTAMs into sTAMs represents an attractive therapeutic strategy. By screening a collection of small molecule compounds we find that inhibition of the β-site amyloid precursor protein cleaving enzyme 1 (BACE1) by MK-8931 potently reprograms pTAMs into sTAMs and promotes macrophage phagocytosis of glioma cells; moreover, low-dose radiation markedly enhances TAM infiltration and synergizes with MK-8931 treatment to suppress malignant growth. BACE1 is preferentially expressed by pTAMs in human GBMs and is required for maintaining pTAM polarization through trans-IL-6-sIL-6R-STAT3 signaling. MK-8931 and other BACE1 inhibitors have been developed for Alzheimer's disease in clinical trials, and have been shown to be safe for humans, these could be potentially streamlined for cancer therapy. Collectively, this study offers a promising therapeutic approach to enhance macrophage-based therapy in GBM. Examination of gene expression inglioma stem cells treated by MK-8931 or control vehicle.