2. Academic Validation
  3. The Novel Phosphatidylinositol-3-Kinase (PI3K) Inhibitor Alpelisib Effectively Inhibits Growth of PTEN-Haploinsufficient Lipoma Cells

The Novel Phosphatidylinositol-3-Kinase (PI3K) Inhibitor Alpelisib Effectively Inhibits Growth of PTEN-Haploinsufficient Lipoma Cells

  • Cancers (Basel). 2019 Oct 17;11(10):1586. doi: 10.3390/cancers11101586.
Anna S Kirstein 1,  Adrien Augustin 2 3,  Melanie Penke 4,  Michele Cea 5 6,  Antje Körner 7,  Wieland Kiess 8,  Antje Garten 9 10
Affiliations

Affiliations

  • 1 Pediatric Research Center, University Hospital for Children and Adolescents, Leipzig University, 04103 Leipzig, Germany. [email protected].
  • 2 Pediatric Research Center, University Hospital for Children and Adolescents, Leipzig University, 04103 Leipzig, Germany. [email protected].
  • 3 Faculty of Medicine, University of Liège, 4000 Liege, Belgium. [email protected].
  • 4 Pediatric Research Center, University Hospital for Children and Adolescents, Leipzig University, 04103 Leipzig, Germany. [email protected].
  • 5 Chair of Hematology, Department of Internal Medicine (DiMI), University of Genoa, 16100 Genoa, Italy. [email protected].
  • 6 IRCCS Polyclinic Hospital San Martino, 16100 Genoa, Italy. [email protected].
  • 7 Pediatric Research Center, University Hospital for Children and Adolescents, Leipzig University, 04103 Leipzig, Germany. [email protected].
  • 8 Pediatric Research Center, University Hospital for Children and Adolescents, Leipzig University, 04103 Leipzig, Germany. [email protected].
  • 9 Pediatric Research Center, University Hospital for Children and Adolescents, Leipzig University, 04103 Leipzig, Germany. [email protected].
  • 10 Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, UK. [email protected].
PMID: 31627436 DOI: 10.3390/cancers11101586
Abstract

Germline mutations in the tumor suppressor gene PTEN cause PTEN Hamartoma Tumor Syndrome (PHTS). Pediatric patients with PHTS frequently develop lipomas. Treatment attempts with the mTORC1 Inhibitor rapamycin were unable to reverse lipoma growth. Recently, lipomas associated with PIK3CA-related overgrowth syndrome were successfully treated with the novel PI3K Inhibitor alpelisib. Here, we tested whether alpelisib has growth-restrictive effects and induces cell death in lipoma cells. We used PTEN-haploinsufficient lipoma cells from three patients and treated them with alpelisib alone or in combination with rapamycin. We tested the effect of alpelisib on viability, proliferation, cell death, induction of senescence, adipocyte differentiation, and signaling at 1-100 µM alpelisib. Alpelisib alone or in combination with rapamycin reduced proliferation in a concentration- and time-dependent manner. No cell death but an induction of senescence was detected after alpelisib incubation for 72 h. Alpelisib treatment led to a reduced phosphorylation of Akt, mTOR, and ribosomal protein S6. Rapamycin treatment alone led to increased Akt phosphorylation. This effect could be reversed by combining rapamycin with alpelisib. Alpelisib reduced the size of lipoma spheroids by attenuating adipocyte differentiation. Since alpelisib was well tolerated in first clinical trials, this drug alone or in combination with rapamycin is a potential new treatment option for PHTS-related adipose tissue overgrowth.

Keywords

AKT; PHTS; PROS; lipoma; mTOR; overgrowth; proliferation; rapamycin; ribosomal protein S6; spheroids.

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