KRAS or BRAF mutations cause hepatic vascular cavernomas treatable with MAP2K-MAPK1 inhibition.

Human hepatic vascular cavernomas, the most common benign tumor of the liver, were described in the mid-1800s, yet the mechanisms for their formation and effective treatments remain unknown. Here, we demonstrate gain-of-function mutations in KRAS or BRAF genes within liver endothelial cells as a causal mechanism for hepatic vascular cavernomas. We identified gain-of-function mutations in KRAS or BRAF genes in pathological liver tissue samples from patients with hepatic vascular cavernomas. Mice expressing these human KRASG12D or BRAFV600E mutations in hepatic endothelial cells recapitulated the human hepatic vascular cavernoma phenotype of dilated sinusoidal capillaries with defective branching patterns. KRASG12D or BRAFV600E induced "zipper-like" contiguous expression of junctional proteins at sinusoidal endothelial cell-cell contacts, switching capillaries from branching to cavernous expansion. Pharmacological or genetic inhibition of the endothelial RAS-MAPK1 signaling pathway rescued hepatic vascular cavernoma formation in endothelial KRASG12D- or BRAFV600E-expressing mice. These results uncover a major cause of hepatic vascular cavernomas and provide a road map for their personalized treatment.