Brain arteriovenous malformations (bAVMs) are a notable cause of intracranial hemorrhage, strongly associated with severe morbidity and mortality. Contemporary treatment options include surgery, stereotactic radiosurgery, and endovascular embolization, each of which has limitations. Hence, development of pharmacological interventions is urgently needed. The recent discovery of the presence of activating Kirsten rat sarcoma (KRAS) viral oncogene homologue mutations in most sporadic bAVMs has opened the door for a more comprehensive understanding of the pathogenesis of bAVMs and has pointed to entirely novel possible therapeutic targets. Herein, we review the status quo of genetics, animal models, and therapeutic approaches in bAVMs.
MohrJPParidesMKStapfC, et al.
Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet2014;
383: 614–621.
2.
MohrJPOverbeyJRHartmannA, et al.
Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Lancet Neurol2020;
19: 573–581.
3.
SpetzlerRFMartinNA.A proposed grading system for arteriovenous malformations. J Neurosurg1986;
65: 476–483.
4.
CatapanoJSFrisoliFANguyenCL, et al.
Intermediate-grade brain arteriovenous malformations and the boundary of operability using the supplemented Spetzler-Martin grading system. J Neurosurg2022;
136: 125–133.
5.
PollockBEFlickingerJCLunsfordLD, et al.
Hemorrhage risk after stereotactic radiosurgery of cerebral arteriovenous malformations. Neurosurgery1996;
38: 652–661.
6.
FriedmanWABlattDLBovaFJ, et al.
The risk of hemorrhage after radiosurgery for arteriovenous malformations. J Neurosurg1996;
84: 912–919.
7.
FrizzelRTFisherWS3rd.Cure, morbidity, and mortality associated with embolization of brain arteriovenous malformations: a review of 1246 patients in 32 series over a 35-year period. Neurosurgery1995;
37: 1031–1039.
8.
WikholmGLundqvistCSvendsenP.Embolization of cerebral arteriovenous malformations: part I – technique, morphology, and complications. Neurosurgery1996;
39: 448–459.
NikolaevSIVetiskaSBonillaX, et al.
Somatic activating KRAS mutations in arteriovenous malformations of the brain. N Engl J Med2018;
378: 250–261.
11.
FishJEFlores SuarezCPBoudreauE, et al.
Somatic gain of KRAS function in the endothelium is sufficient to cause vascular malformations that require MEK but not PI3K signaling. Circ Res2020;
127: 727–743.
12.
JakobssonLArthurHM.Oncogenes in brain arteriovenous malformations. Circ Res2020;
127: 744–746.
13.
PangMZhangGShangC, et al.
Advances in the study of KRAS in brain arteriovenous malformation. Cerebrovasc Dis2024;
53: 767–775.
14.
De LucaAMaielloMRD'AlessioA, et al.
The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets2012;
16 Suppl 2: S17–S27.
15.
QueisserASerontEBoonLM, et al.
Genetic basis and therapies for vascular anomalies. Circ Res2021;
129: 155–173.
16.
FraissenonABayardCMorinG, et al.
Sotorasib for vascular malformations associated with KRAS G12C mutation. N Engl J Med2024;
391: 334–342.
17.
TuTYuJJiangC, et al.
Somatic BrafV600E mutation in the cerebral endothelium induces brain arteriovenous malformations. Angiogenesis2024;
27: 441–460.
18.
HongTYanYLiJ, et al.
High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations. Brain2019;
142: 23–34.
19.
OkaMKushamaeMAokiT, et al.
KRAS G12D or G12V mutation in human brain arteriovenous malformations. World Neurosurg2019;
126: e1365–e1373.
20.
PriemerDSVortmeyerAOZhangS, et al.
Activating KRAS mutations in arteriovenous malformations of the brain: frequency and clinicopathologic correlation. Hum Pathol2019;
89: 33–39.
21.
GossJAHuangAYSmithE, et al.
Somatic mutations in intracranial arteriovenous malformations. PLoS One2019;
14: e0226852.
22.
GaoSNelsonJWeinsheimerS, et al.
Somatic mosaicism in the MAPK pathway in sporadic brain arteriovenous malformation and association with phenotype. J Neurosurg2022;
136: 148–155.
23.
BameriOSalarzaeiMParooieF.KRAS/BRAF mutations in brain arteriovenous malformations: a systematic review and meta-analysis. Interv Neuroradiol2021;
27: 539–546.
24.
ParkESKimSHuangS, et al.
Selective endothelial hyperactivation of oncogenic KRAS induces brain arteriovenous malformations in mice. Ann Neurol2021;
89: 926–941.
25.
NguyenH-LBoonLMVikkulaM.Trametinib as a promising therapeutic option in alleviating vascular defects in an endothelial KRAS-induced mouse model. Hum Mol Genet2023;
32: 276–289.
26.
MusterRKoNSmithW, et al.
Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation. BMJ Neurol Open2021;
3: e000114.
27.
CoxADFesikSWKimmelmanAC, et al.
Drugging the undruggable RAS: mission possible?Nat Rev Drug Discov2014;
13: 828–851.
28.
MartinelliEMorgilloFTroianiT, et al.
Cancer resistance to therapies against the EGFR-RAS-RAF pathway: the role of MEK. Cancer Treat Rev2017;
53: 61–69.
29.
AbeHKikuchiSHayakawaK, et al.
Discovery of a highly potent and selective MEK inhibitor: GSK1120212 (JTP-74057 DMSO solvate). ACS Med Chem Lett2011;
2: 320–324.
30.
EdwardsEAPhelpsASCookeD, et al.
Monitoring arteriovenous malformation response to genotype-targeted therapy. Pediatrics2020;
146: e20193206.
31.
HauschildAGrobJJDemidovLV, et al.
Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, openlabel, phase 3 randomised controlled trial. Lancet2012;
380: 358–365.
32.
FraustroMOlsenBKhatibZ.Response to dabrafenib and tramatenib in an extra-cranial AVM with BRAF V600E mutation. Blood2023;
142: 5418–5418.
33.
RobertCKaraszewskaBSchachterJ, et al.
Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med2015;
372: 30–39.
34.
WalkerEJSuHShenF, et al.
Bevacizumab attenuates VEGF-induced angiogenesis and vascular malformations in the adult mouse brain. Stroke2012;
43: 1925–1930.
35.
LuoJSoliminiNLElledgeSJ.Principles of cancer therapy: oncogene and non-oncogene addiction. Cell2009;
136: 823–837.
