2. Academic Validation
  3. Somatic PIK3R1 mutations in the iSH2 domain are accessible to PI3Kα inhibition

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

  • EMBO Mol Med. 2025 Jul;17(7):1556-1574. doi: 10.1038/s44321-025-00249-9.
Gabriel Morin # 1 2 3,  Alexandre P Garneau # 1 2,  Nabiha Bouzakher 1 2,  Louise Ségot 4,  Antoine Fraissenon 2 5 6 7,  Amélie Blondel 1 2,  Florence Petit 8,  Caroline Chopinet 9,  Franck Mayeux 1 2,  Pierre Fayoux 10,  Anne Dompmartin 11,  Christine Bodemer 1 12,  Estelle Balducci 1 13,  Sophie Kaltenbach 1 13,  Patrick Villarese 13,  Vahid Asnafi 1 2 13,  Christophe Legendre 1 14,  Christine Broissand 15,  Sylvie Fraitag 16,  Chloé Quelin 17,  Nicolas Goudin 18,  Laurent Guibaud 2 5,  Guillaume Canaud 19 20 21
Affiliations

Affiliations

  • 1 Université Paris Cité, Paris, France.
  • 2 INSERM U1151, Institut Necker-Enfants Malades, Paris, France.
  • 3 Unité de Médecine Translationnelle et Thérapies Ciblées, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
  • 4 Polytech Nice Sophia, Université Côte d'Azur, Nice, France.
  • 5 Service d'Imagerie Pédiatrique, Hôpital Femme-Mère-Enfant, HCL, Bron, France.
  • 6 CREATIS UMR 5220, Villeurbanne, 69100, France.
  • 7 Service de Radiologie Mère-Enfant, Hôpital Nord, Saint Etienne, France.
  • 8 Clinique de Génétique, CHU de Lille, Lille, 59000, France.
  • 9 Service de Physiologie & Explorations Fonctionnelles Cardiovasculaires, CHU de Lille, Lille, 59000, France.
  • 10 Service d'ORL, CHU de Lille, Lille, 59000, France.
  • 11 Service de Dermatologie, CHU Côte de Nacre, Caen, 14033, France.
  • 12 Service de Dermatologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
  • 13 Laboratoire d'Oncohématologie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
  • 14 Service de Néphrologie, Transplantation Adultes, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
  • 15 Pharmacie, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
  • 16 Service d'Anatomie Pathologique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
  • 17 Service de Génétique Clinique, Centre de Référence Anomalies du Développement de l'Ouest, CHU Rennes, Rennes, France.
  • 18 Structure Fédérative de Recherche Necker, INSERM US24,-CNRS UAR 3633, Institut Necker-Enfants Malades, Paris, France.
  • 19 Université Paris Cité, Paris, France. guillaume.canaud@inserm.fr.
  • 20 INSERM U1151, Institut Necker-Enfants Malades, Paris, France. guillaume.canaud@inserm.fr.
  • 21 Unité de Médecine Translationnelle et Thérapies Ciblées, Hôpital Necker-Enfants Malades, AP-HP, Paris, France. guillaume.canaud@inserm.fr.
  • # Contributed equally.
PMID: 40389643 DOI: 10.1038/s44321-025-00249-9
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.

Keywords

Alpelisib; Overgrowth Syndrome; PIK3R1-Related Disorders; Vascular Malformations; p85.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15244
    99.95%, PI3Kα Inhibitor