Dual MAPK/VEGF inhibition for KRAS-mutated brain arteriovenous malformations

Brain arteriovenous malformations (bAVMs) are rare but potentially devastating cerebrovascular lesions. Activating KRAS mutations are common in sporadic bAVMs, but their clinical implications remain unclear. The aim of this study was to investigate a novel therapeutic strategy for hemorrhagic bAVMs based on dual inhibition of the mitogen-activated protein kinase (MAPK) and vascular endothelial growth factor (VEGF) pathways using an engineered mouse model with a titratable KRASG12V-GFP transgene.

The AAV-BR1-CAG vector was used to deliver a KRASG12V-GFP transgene specifically to cerebral endothelial cells. Mice received 5 × 107 to 5 × 1010 genome copies of the vector, and bAVM formation, intracerebral hemorrhage (ICH), and overall survival were assessed. Mice with established hemorrhagic bAVMs were subsequently treated with trametinib (MEK inhibitor) or RMC-7977 (RAS inhibitor), with or without an anti-mouse VEGF antibody, starting 4 weeks after viral delivery. Overall survival was assessed.

Selective overexpression of KRASG12V-GFP in cerebral endothelial cells led to the formation of bAVMs in a dose-dependent manner. Mice that received the highest transgene dose developed significantly more bAVMs, exhibited a higher ICH burden, and had worse overall survival compared with those that received lower transgene doses. In mice receiving the highest transgene dose, trametinib alone modestly improved the median overall survival (8.4 weeks vs 6.4 weeks, p = 0.049), while single-agent RMC-7977 showed no significant benefit. Anti-VEGF therapy alone reduced survival (6.9 weeks vs 9.6 weeks, p = 0.044). However, combination therapy with trametinib or RMC-7977 and anti-VEGF antibody significantly prolonged survival, with the most pronounced benefit seen in the RMC-7977 plus anti-VEGF group (13.1 weeks vs 6.7 weeks in controls, p = 0.024).

Our findings suggest that, in addition to promoting bAVM formation, KRAS mutations in cerebral endothelial cells might be causally implicated in bAVM rupture. Additionally, concomitant inhibition of the MAPK and VEGF pathways could be a promising novel therapeutic strategy for KRAS-mutated bAVMs.