The kinase inhibitor dabrafenib halts progression of cerebral cavernous malformations in a BRAF-independent manner.

Cerebral cavernous malformations (CCMs) constitute the second most common type of intracranial vascular malformations. Cavernomas arise because of somatic or autosomal dominant inherited loss-of-function mutations in CCM genes, forming fragile mulberry-like malformed blood vessel structures that are prone to leak and break. Treatment is limited to surgical removal of solitary cavernomas, and because patients often present with multiple lesions, pharmacological alternatives to surgery are needed. We performed a high-throughput screen of 5200 bioactive molecules in programmed cell death 10 (PDCD10 or CCM3)-deficient mouse endothelial cells, coupled to automated image analysis. This screen identified dabrafenib, a clinically approved BRAF inhibitor, as a compound that restored cell-cell junctions and vascular barrier properties of CCM3-deficient endothelial cells. The potential translatability of dabrafenib was tested in acute and chronic CCM mouse models, where it reduced cerebral lesion burden and suppressed lesion permeability. Dabrafenib also rescued abnormal structural defects present in the developing retina vasculature in an acute CCM mouse model. Mechanistically, dabrafenib targeted extracellular regulated kinase (ERK)5-Krüppel-like factor (KLF)2/4 signaling and suppressed F-actin stress fiber formation in human brain endothelial cells, two potentially independent and central molecular processes involved in CCM pathology. Silencing BRAF did not prevent dabrafenib-induced KLF2/4 inhibition or restoration of cell-cell junctions, suggesting that its dual therapeutic outcome is independent of BRAF pathway inhibition. In conclusion, dabrafenib is a low-molecular weight compound that inhibits cavernoma pathogenesis, suggesting that CCMs could be treated with dabrafenib to block cavernoma growth and vascular leakage.