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 M
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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:84609 |
| Date | 06 April 2023 |
| Creators | Kirstein, Anna S., Augustin, Adrien, Penke, Melanie, Cea, Michele, Körner, Antje, Kiess, Wieland, Garten, Antje |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2072-6694, 1586 |
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