ArticleOncotarget2017
The effect of rapamycin, NVP-BEZ235, aspirin, and metformin on PI3K/AKT/mTOR signaling pathway of PIK3CA-related overgrowth spectrum (PROS).
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 23 citations in OpenAlex.
- A visual analysis of research hotspots and trends on macrodactyly between 2005 and 2024.Orphanet journal of rare diseases · 2025Article
- Nanomaterials targeting cancer stem cells to overcome drug resistance and tumor recurrence.Frontiers in oncology · 2025Review
- Delineation of the phenotypes and genotypes of PIK3CA-related overgrowth spectrum in East asians.Molecular genetics and genomics : MGG · 2024Article
- Macrodactyly.Children (Basel, Switzerland) · 2024Review
- Case report: Progressive pulmonary artery hypertension in a case of megalencephaly-capillary malformation syndrome.Frontiers in genetics · 2023Article
- Activating PIK3CA mutation promotes adipogenesis of adipose-derived stem cells in macrodactyly via up-regulation of E2F1.Cell death & disease · 2020Article
- PIK3CA mutations in lipomatosis of nerve with or without nerve territory overgrowth.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2020Article
- Novel mTOR Inhibitor Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeting Agents.OncoTargets and therapy · 2020Article
- Virtual Screening and Optimization of Novel mTOR Inhibitors for Radiosensitization of Hepatocellular Carcinoma.Drug design, development and therapy · 2020Article
- Safety and efficacy of low-dose sirolimus in the PIK3CA-related overgrowth spectrum.Genetics in medicine : official journal of the American College of Medical Genetics · 2019Article
- Expression and significance of EBV, ARID1A and PIK3CA in gastric carcinoma.Molecular medicine reports · 2019Article
- A postzygotic KRAS mutation in a patient with Schimmelpenning syndrome presenting with lipomatosis, renovascular hypertension, and diabetes mellitus.Journal of human genetics · 2019Article
- Cellular and molecular mechanisms of PIK3CA-related vascular anomalies.Vascular biology (Bristol, England) · 2019Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway is critical for cellular growth and metabolism. Recently, mosaic or segmental overgrowth, a clinical condition caused by heterozygous somatic activating mutations in PIK3CA, was established as PIK3CA-related overgrowth spectrum (PROS). In this study, we report a Japanese female diagnosed with PROS, who presented with hyperplasia of the lower extremities, macrodactyly, multiple lipomatosis, and sparse hair. Sequencing and mutant allele frequency analysis of PIK3CA from affected tissues revealed that the patient had a heterozygous mosaic mutation (c.3140A>G [p.H1047R]) in PIK3CA and that there were higher mutant allele frequencies from samples with a larger amount of subcutaneous adipose tissue. We established two fibroblast cell lines from the patient, harboring high and low frequencies of the mosaic mutation, in which AKT and S6 showed higher level of phosphorylation compared with three control fibroblasts, indicating that PI3K/AKT/mTOR signaling is activated. We assessed the therapeutic effects of four compounds (rapamycin, NVP-BEZ235, aspirin, and metformin) on PI3K/AKT/mTOR signaling pathway and cell growth. All four compounds suppressed S6 phosphorylation and inhibited cell growth of the patient-derived fibroblast cell lines. However, only metformin mildly inhibited the growth of the control fibroblast cell lines. Since PROS is a congenital disorder, drugs for therapy should take into consideration the natural growth of children. Thus, metformin is a candidate drug for treating PROS in growing children.
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