Inhibition of triple negative breast cancer-associated inflammation, tumor growth and brain colonization by targeting monoacylglycerol lipase

While the prevalence of breast cancer metastasis in the brain is significantly higher in triple negative breast cancers (TNBCs), there is a lack of novel and/or improved therapies for these patients. Monoacylglycerol lipase (MAGL) is a hydrolase involved in lipid metabolism that catalyzes the degradation of 2-arachidonoylglycerol (2-AG) linked to generation of pro- and anti-inflammatory molecules. Here, we targeted MAGL in TNBCs, using a potent carbamate-based inhibitor AM9928 (hMAGL IC50 = 9 nM) with prolonged pharmacodynamic effects (46 h of target residence time). AM9928 blocked TNBC cell adhesion and transmigration across human brain microvascular endothelial cells (HBMECs) in 3D co-cultures. In addition, AM9928 inhibited the secretion of IL-6, IL-8, and VEGF-A from TNBC cells. TNBC-derived exosomes activated HBMECs resulting in secretion of elevated levels of IL-8 and VEGF, which were inhibited by AM9928. Using in vivo studies of syngeneic GFP-4T1-BrM5 mammary tumor cells, AM9928 inhibited tumor growth in the mammary fat pads and attenuated blood brain barrier (BBB) permeability changes, resulting in reduced TNBC colonization in brain. Together, these results support the potential clinical application of MAGL inhibitors as novel treatments for TNBC.

Automated summary

This study found that the use of MAGL inhibitor AM9928 can effectively block the adhesion and migration of TNBC cells, reduce the secretion of pro-inflammatory factors by cells, and inhibit the activation of HBMECs and cytokine secretion caused by TNBC. Animal experiments showed that AM9928 can inhibit the growth of mammary tumors in the mammary fat pads and reduce the permeability changes of the blood brain barrier, thus reducing the metastasis of TNBC in the brain. These findings suggest that MAGL inhibitors have the potential to be a novel strategy for TNBC treatment.