Trametinib inhibits lymphatic vessel invasion of bone in a mouse model of Gorham-Stout disease.

OBJECTIVE

Gorham-Stout disease (GSD) is a rare lymphatic anomaly that can be caused by somatic activating mutations in . This discovery has led investigators to suggest that MEK inhibitors could be a novel treatment for GSD. However, the effect of MEK inhibitors on bone disease in animal models of GSD has not been investigated. We recently reported that mice exhibit a phenotype that resembles GSD. mice overexpress VEGF-C in bone, which stimulates the development of lymphatic vessels in bone and the gradual loss of cortical bone. The objective of this study was to characterize the effect of trametinib, an FDA-approved MEK1/2 inhibitor, on lymphangiogenesis and osteolysis in mice.

METHODS

Immunoblotting was performed to assess the effect of trametinib on VEGF-C-induced phosphorylation of ERK1/2, AKT, and S6 in primary human lymphatic endothelial cells (LECs). Prevention and intervention experiments were performed to determine the effect of trametinib on lymphangiogenesis and osteolysis in mice.

RESULTS

We found that trametinib blocked VEGF-C-induced phosphorylation of ERK1/2 in primary human LECs. We also found that trametinib prevented VEGF-C-induced lymphatic invasion of bone and cortical bone loss in mice. Additionally, trametinib slowed the progression of disease in mice with established disease. However, it did not reverse disease in mice.

CONCLUSION

Our results show trametinib impacts bone disease in mice. These findings further support the testing of MEK inhibitors in patients with GSD and other RAS pathway-driven complex lymphatic anomalies with bone involvement.