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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.
Sotorasib, a KRAS G12C inhibitor, effectively reduced vascular malformation size and improved survival in mouse models. Clinical trials showed similar benefits for patients with KRAS G12C-related arteriovenous malformations.
Area of Science:
- Vascular Biology
- Oncology
- Pharmacology
Background:
- Gain-of-function KRAS mutations are common in arteriovenous malformations (AVMs).
- The progression mechanisms of KRAS-driven AVMs are not fully understood.
- Currently, no approved treatments exist for these conditions.
Purpose of the Study:
- To investigate the therapeutic potential of sotorasib, a KRAS G12C inhibitor, for KRAS-driven vascular malformations.
- To evaluate the efficacy of sotorasib in preclinical models and human patients.
Main Methods:
- Utilized two mouse models with mosaic Kras G12C mutations to assess sotorasib's impact on vascular malformation volume and survival.
- Administered sotorasib to two adult patients diagnosed with severe KRAS G12C-related AVMs.
Main Results:
- Sotorasib significantly reduced vascular malformation volume and improved survival in mouse models.
- Both treated patients experienced rapid symptom alleviation and a decrease in AVM size.
- KRAS G12C inhibition demonstrated therapeutic efficacy in a clinical setting.
Conclusions:
- Targeting KRAS G12C with sotorasib represents a promising therapeutic strategy for patients with KRAS G12C-related vascular malformations.
- Sotorasib offers a potential new treatment avenue for a previously untreatable condition.
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