Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibition
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. Curren...
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Springer Nature
2025-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.1038/s44321-025-00249-9 |
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| author | Gabriel Morin Alexandre P Garneau Nabiha Bouzakher Louise Ségot Antoine Fraissenon Amélie Blondel Florence Petit Caroline Chopinet Franck Mayeux Pierre Fayoux Anne Dompmartin Christine Bodemer Estelle Balducci Sophie Kaltenbach Patrick Villarese Vahid Asnafi Christophe Legendre Christine Broissand Sylvie Fraitag Chloé Quelin Nicolas Goudin Laurent Guibaud Guillaume Canaud |
| author_facet | Gabriel Morin Alexandre P Garneau Nabiha Bouzakher Louise Ségot Antoine Fraissenon Amélie Blondel Florence Petit Caroline Chopinet Franck Mayeux Pierre Fayoux Anne Dompmartin Christine Bodemer Estelle Balducci Sophie Kaltenbach Patrick Villarese Vahid Asnafi Christophe Legendre Christine Broissand Sylvie Fraitag Chloé Quelin Nicolas Goudin Laurent Guibaud Guillaume Canaud |
| author_sort | Gabriel Morin |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b8cbdf1b2bbf40249c838fa67b7c5be9 |
| institution | DOAJ |
| issn | 1757-4684 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-b8cbdf1b2bbf40249c838fa67b7c5be92025-08-20T03:05:53ZengSpringer NatureEMBO Molecular Medicine1757-46842025-05-011771556157410.1038/s44321-025-00249-9Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibitionGabriel Morin0Alexandre P Garneau1Nabiha Bouzakher2Louise Ségot3Antoine Fraissenon4Amélie Blondel5Florence Petit6Caroline Chopinet7Franck Mayeux8Pierre Fayoux9Anne Dompmartin10Christine Bodemer11Estelle Balducci12Sophie Kaltenbach13Patrick Villarese14Vahid Asnafi15Christophe Legendre16Christine Broissand17Sylvie Fraitag18Chloé Quelin19Nicolas Goudin20Laurent Guibaud21Guillaume Canaud22Université Paris CitéUniversité Paris CitéUniversité Paris CitéPolytech Nice Sophia, Université Côte d’AzurINSERM U1151, Institut Necker-Enfants MaladesUniversité Paris CitéClinique de Génétique, CHU de LilleService de Physiologie & Explorations Fonctionnelles Cardiovasculaires, CHU de LilleUniversité Paris CitéService d’ORL, CHU de LilleService de Dermatologie, CHU Côte de NacreUniversité Paris CitéUniversité Paris CitéUniversité Paris CitéLaboratoire d’Oncohématologie, Hôpital Necker-Enfants Malades, AP-HPUniversité Paris CitéUniversité Paris CitéPharmacie, Hôpital Necker-Enfants Malades, AP-HPService d’Anatomie Pathologique, Hôpital Necker-Enfants Malades, AP-HPService de Génétique Clinique, Centre de Référence Anomalies du Développement de l’Ouest, CHU RennesStructure Fédérative de Recherche Necker, INSERM US24,-CNRS UAR 3633, Institut Necker-Enfants MaladesINSERM U1151, Institut Necker-Enfants MaladesUniversité Paris CitéAbstract 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.https://doi.org/10.1038/s44321-025-00249-9PIK3R1-Related Disordersp85Vascular MalformationsOvergrowth SyndromeAlpelisib |
| spellingShingle | Gabriel Morin Alexandre P Garneau Nabiha Bouzakher Louise Ségot Antoine Fraissenon Amélie Blondel Florence Petit Caroline Chopinet Franck Mayeux Pierre Fayoux Anne Dompmartin Christine Bodemer Estelle Balducci Sophie Kaltenbach Patrick Villarese Vahid Asnafi Christophe Legendre Christine Broissand Sylvie Fraitag Chloé Quelin Nicolas Goudin Laurent Guibaud Guillaume Canaud Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibition EMBO Molecular Medicine PIK3R1-Related Disorders p85 Vascular Malformations Overgrowth Syndrome Alpelisib |
| title | Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibition |
| title_full | Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibition |
| title_fullStr | Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibition |
| title_full_unstemmed | Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibition |
| title_short | Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibition |
| title_sort | somatic pik3r1 mutations in the ish2 domain are accessible to pi3kα inhibition |
| topic | PIK3R1-Related Disorders p85 Vascular Malformations Overgrowth Syndrome Alpelisib |
| url | https://doi.org/10.1038/s44321-025-00249-9 |
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