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Sotorasib for Vascular Malformations Associated with KRAS G12C Mutation
Antoine Fraissenon1, Charles Bayard1, Gabriel Morin1
1From Service d'Imagerie Pédiatrique, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Bron (A.F., L.G.), CREATIS Unité Mixte de Recherche 5220, Villeurbanne (A.F.), INSERM Unité 1151, Institut Necker-Enfants Malades (A.F., C. Bayard, G.M., S.B., C.H., S.P., L.Z., S.L., M.F., V.A., L.G., G.C.), Université Paris Cité (C. Bayard, G.M., S.B., C.H., S.P., L.Z., S.L., M.F., T.B., O.N., C.L., E.B., V.A., L.G., G.C.), Unité de Médecine Translationnelle et Thérapies Ciblées (C. Bayard, G.M., C.H., S.P., L.Z., S.L., M.F., L.G., G.C.), Service de Neurochirurgie Pédiatrique (S.B., T.B.), Service de Néphrologie et Transplantation Adultes (C.L.), and Laboratoire d'Oncohématologie (S.K., E.B., P.V., V.A.), Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Département de Neuroradiologie, Hôpital Lariboisière, AP-HP (A.B.), and Service de Neuroradiologie Interventionnelle, Hôpital Sainte Anne, AP-HP (O.N.), Paris, Service de Radiologie Mère-Enfant, Hôpital Nord, Saint Etienne (A.F.), the Respiratory Department and Early phase EPSILYON Est, Louis Pradel Hospital, Oncopharmacology Laboratory, Cancer Research Center of Lyon, Unité Mixte de Recherche INSERM 1052, Center National de la Recherche Scientifique (CNRS) 5286 (M. Duruisseaux), Centre de Recherche en Neurosciences de Lyon, INSERM Unité 1028, CNRS Unité Mixte de Recherche 5292 (M. Delous, C. Boitel), and the Institute of Pharmaceutical and Biological Sciences (L.P.), Université Claude Bernard Lyon 1, and Service d'Anatomie Pathologique, Hôpital Edouard Herriot, Hospices Civils de Lyon (P.-P.B.), Lyon, the Circulating Cancer Program, Cancer Institute (L.P.), and Laboratoire de Biologie Médicale Multi Sites du Centre Hospitalier Universitaire de Lyon, Service de Biochimie et Biologie Moléculaire (L.P.), Hospices Civils de Lyon, and the Center for Innovation in Cancerology of Lyon, EA 3738, Faculty of Medicine and Maieutic Lyon Sud, Université Claude Bernard Lyon 1 (L.P.), Oullins-Pierre-Bénite - all in France.
Abstract:
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.).
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