RNA-seq studies in dabrafenib treated endothelial cells

The potential translatability of dabrafenib was tested in vivo, where it reduced cerebral lesion burden and suppressed lesion permeability, reducing perivascular plasma protein depositions. Dabrafenib also rescued abnormal structural defects present in the developing retina vasculature. Mechanistically, dabrafenib targeted extracellular regulated kinase (ERK)5-Krüppel like factor (KLF)2/4 signaling pathway and suppressed F-actin stress fiber formation, two potentially independent and central molecular processes involved in CCM pathology.

Dabrafenib is a kinase inhibitor indicated for the treatment of tumors with BRAF V600E mutations. However, silencing of BRAF did not interfere with dabrafenib-induced KLF2/4 inhibition and restoration of cell-cell junctions, suggesting that its dual therapeutic outcome is independent of BRAF pathway inhibition. In conclusion, dabrafenib is a small molecular weight compound with marked inhibitory effects on cavernoma pathogenesis suggesting that CCMs could be treated with dabrafenib to block cavernoma growth and vascular leakage.