Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibition

Mutations in PIK3R1 have recently been identified in patients with overgrowth syndromes and complex vascular malformations. PIK3R1 encodes p85α which acts as the regulatory subunit of the lipid kinase PI3Kα. PIK3R1 mutations result in the excessive activation of the AKT/mTOR pathway. Currently, there are no approved treatments specifically dedicated to patients with PIK3R1 mutations, and medical care primarily focuses on managing symptoms. In this study, we identified three patients, including two children, who had mosaic somatic PIK3R1 mutations affecting the iSH2 domain, along with severe associated symptoms that were unsuccessfully treated with rapamycin. We conducted in vitro experiments to investigate the impact of these mutations, including a double PIK3R1 mutation in cis observed in one patient. Our findings revealed that p85α mutants in the iSH2 domain showed sensitivity to alpelisib, a pharmacological inhibitor of PI3Kα. Based on these findings, we received authorization to administer alpelisib to all three patients. Following drug introduction, patients rapidly demonstrated clinical improvement, pain, fatigue and inflammatory flares were attenuated. Magnetic Resonance Imaging showed a mean decrease of 22.67% in the volume of vascular malformations over twelve months of treatment with alpelisib. No drug-related adverse events were reported during the course of the study. In conclusion, this study provides support for the use of PI3Kα inhibition as a promising therapeutic approach for individuals with PIK3R1-related anomalies.

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Publication Details

Journal
EMBO Molecular Medicine
Published
2025-05-19
DOI
https://doi.org/10.1038/s44321-025-00249-9
Citations
1
Primary Topic
Vascular Malformations and Hemangiomas
Type
article
Field-Weighted Citation Impact
2.01

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article

Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibition

Patrick Villarèse, Caroline Chopinet, Antoine Fraissenon, Florence Petit et al.
1 citations
EMBO Molecular Medicine
Vascular Malformations and Hemangiomas
2.01
article

Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibition

Patrick Villarèse, Caroline Chopinet, Antoine Fraissenon, Florence Petit, G Morin, Laurent Guibaud, Christine Broissand, A. Dompmartin, Vahid Asnafi, Nicolas Goudin, P. Fayoux, Estelle Balducci, Christophe Legendre, Chloé Quēlin, Alexandre P. Garneau, Sophie Kaltenbach, Franck Mayeux, Nabiha Bouzakher, Sylvie Fraïtag, Guillaume Canaud, Amélie Blondel, Christine Bodemer, Louise Ségot
article en
1 citations

Abstract

Mutations in PIK3R1 have recently been identified in patients with overgrowth syndromes and complex vascular malformations. PIK3R1 encodes p85α which acts as the regulatory subunit of the lipid kinase PI3Kα. PIK3R1 mutations result in the excessive activation of the AKT/mTOR pathway. Currently, there are no approved treatments specifically dedicated to patients with PIK3R1 mutations, and medical care primarily focuses on managing symptoms. In this study, we identified three patients, including two children, who had mosaic somatic PIK3R1 mutations affecting the iSH2 domain, along with severe associated symptoms that were unsuccessfully treated with rapamycin. We conducted in vitro experiments to investigate the impact of these mutations, including a double PIK3R1 mutation in cis observed in one patient. Our findings revealed that p85α mutants in the iSH2 domain showed sensitivity to alpelisib, a pharmacological inhibitor of PI3Kα. Based on these findings, we received authorization to administer alpelisib to all three patients. Following drug introduction, patients rapidly demonstrated clinical improvement, pain, fatigue and inflammatory flares were attenuated. Magnetic Resonance Imaging showed a mean decrease of 22.67% in the volume of vascular malformations over twelve months of treatment with alpelisib. No drug-related adverse events were reported during the course of the study. In conclusion, this study provides support for the use of PI3Kα inhibition as a promising therapeutic approach for individuals with PIK3R1-related anomalies.

EMBO Molecular MedicineVol. 17(7)
Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Côte d'Azur (FR), Université Paris Cité (FR), Centre Hospitalier Universitaire de Lille (FR), Hôpital Femme Mère Enfant (FR), Institut Necker Enfants Malades (FR), Lille’s Cardiology Hospital (FR), Sorbonne Paris Cité (FR), Assistance Publique – Hôpitaux de Paris (FR), Hospices Civils de Lyon (FR), Centre Hospitalier Universitaire de Caen Normandie (FR), Hôpital Nord (FR), CIC Rennes (FR), Institut de génétique et de développement de Rennes (FR), Groupe Hospitalier de l'Institut Catholique de Lille (FR), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (FR)
Fondation Simone et Cino Del Duca, Fondation Maladies Rares, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Assistance Publique - Hôpitaux de Paris, Fondation pour la Recherche Médicale, Fondation Bettencourt Schueller, Fondation Schlumberger pour l’Education et la Recherche, HORIZON EUROPE European Research Council
Good health and well-being
Openalex Percentile: Top 16%
Vascular Malformations and Hemangiomas
2.01
DOIOpen Access PDFOpenAlex
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