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

Abstract

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.

Pathological MAPK activation–mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib

“…Here, we demonstrate that KRAS G12D gain-of-function mutation drives pulmonary and intercostal lymphangiectasia without modulating the rate of lymphatic endothelial cell proliferation (Figure 2, D-F), consistent with Mulliken and Glowacki's binary characterization of vascular anomalies described in 1982 (90). This study, and previous literature reports from our group and others, further highlight nononcogenic roles of KRAS gain-of-function mutations (91)(92)(93). KRAS G12D mutations drive activation of RAF-MAP2K, which in turn phosphorylates and activates MAPK, the effector node of KRAS/MAPK signaling pathway (94).…”

Cutaneous and hepatic vascular lesions due to a recurrent somatic GJA4 mutation reveal a pathway for vascular malformation

“… 11 , 12 In a recent study, 14 of 39 HH lesions (36%) were found via targeted sequencing to harbor canonical KRAS (G12D, G12S, G13D, or G13S) or BRAF (V600M) mutations, but many cases in the skin and liver remain mutation-unknown, and we sought to identify other genetic causes. 13 …”

KRAS protein expression becomes progressively restricted during embryogenesis and in adulthood

“…Interestingly, we observe KRAS expression in liver sinusoidal cells, a specialized endothelial cell type found notably in the organ. This observation may be linked to the discovery that KRAS mutations in these cells specifically lead to the development of hepatic vascular cavernomas ( Janardhan et al, 2020 ), a benign tumor of the liver characterized by the presence of dilated endothelial-lined vascular spaces.…”