RESUMO
KRAS gain-of-function mutations are frequently observed in sporadic arteriovenous malformations. The mechanisms underlying the progression of such KRAS-driven malformations are still incompletely understood, and no treatments for the condition are approved. Here, we show the effectiveness of sotorasib, a specific KRAS G12C inhibitor, in reducing the volume of vascular malformations and improving survival in two mouse models carrying a mosaic Kras G12C mutation. We then administered sotorasib to two adult patients with severe KRAS G12C-related arteriovenous malformations. Both patients had rapid reductions in symptoms and arteriovenous malformation size. Targeting KRAS G12C appears to be a promising therapeutic approach for patients with KRAS G12C-related vascular malformations. (Funded by the European Research Council and others.).
Assuntos
Malformações Arteriovenosas , Proteínas Proto-Oncogênicas p21(ras) , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/diagnóstico por imagem , Malformações Arteriovenosas/tratamento farmacológico , Malformações Arteriovenosas/genética , Modelos Animais de Doenças , Mutação com Ganho de Função , Mutação , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Piridinas/uso terapêutico , Pirimidinas , Fármacos Cardiovasculares/uso terapêutico , Adulto JovemRESUMO
Central nervous system (CNS) dural arteriovenous fistulas (DAVF) have been reported in PTEN-related hamartoma tumor syndrome (PHTS). However, PHTS-associated DAVF remain an underexplored field of the PHTS clinical landscape. Here, we studied cases with a PTEN pathogenic variant identified between 2007 and 2020 in our laboratory (n = 58), and for whom brain imaging was available. Two patients had DAVF (2/58, 3.4%), both presenting at advanced stages: a 34-year-old man with a left lateral sinus DAVF at immediate risk of hemorrhage, and a 21-year-old woman with acute intracranial hypertension due to a torcular DAVF. Interestingly, not all patients had 3D TOF/MRA, the optimal sequences to detect DAVF. Early diagnosis of DAVF can be lifesaving, and is easier to treat compared to developed, proliferative, or complex lesions. As a result, one should consider brain MRI with 3D TOF/MRA in PHTS patients at genetic diagnosis, with subsequent surveillance on a case-by-case basis.