The novel phosphatidylinositol-3-Kinase (PI3K) inhibitor alpelisib effectively inhibits growth of PTEN-haploinsufficient lipoma cells

Anna S. Kirstein, Adrien Augustin, Melanie Penke, Michele Cea, Antje Körner, Wieland Kiess, Antje Garten

Research output: Contribution to journalArticlepeer-review

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 concentrationand 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.

Original languageEnglish
Article number1586
JournalCancers
Volume11
Issue number10
DOIs
Publication statusPublished - Oct 2019

Keywords

  • AKT
  • Lipoma
  • MTOR
  • Overgrowth
  • PHTS
  • Proliferation
  • PROS
  • Rapamycin
  • Ribosomal protein S6
  • Spheroids

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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