Somatic PIK3R1 mutations in the iSH2 domain are accessible to PIK3CA inhibition

ABSTRACT: Mutations in PIK3R1 have been identified in patients with overgrowth syndromes and complex vascular malformations. PIK3R1 encodes p85 which acts as the regulatory subunit of the lipid kinase PI3K. PIK3R1 mutations result in the excessive activation of the AKT/mTOR pathway. There are no approved treatments specifically dedicated to patients with PIK3R1 mutations. Here, 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. Using in vitro experiments, we observed that p85α mutation in the iSH2 domain showed sensitivity to alpelisib, a pharmacological inhibitor of PI3Kα. Based on these findings, we received authorization to administer alpel

SUBMITTER: Gabriel Morin 

PROVIDER: S-SCDT-10_1038-S44321-025-00249-9 | biostudies-other |

REPOSITORIES: biostudies-other