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@ARTICLE{Metselaar:292537,
author = {D. S. Metselaar and M. H. Meel and J. R. Goulding and A. du
Chatinier and L. Rigamonti and P. Waranecki and N.
Geisemeyer$^*$ and M. C. de Gooijer and M. Breur and J.
Koster and S. E. M. Veldhuijzen van Zanten and M. Bugiani
and N. E. Franke and A. Reddy and P. Wesseling and G. J. L.
Kaspers and E. Hulleman},
title = {{G}emcitabine therapeutically disrupts essential
{SIRT}1-mediated p53 repression in atypical
teratoid/rhabdoid tumors.},
journal = {Cell reports / Medicine},
volume = {5},
number = {9},
issn = {2666-3791},
address = {Maryland Heights, MO},
publisher = {Elsevier},
reportid = {DKFZ-2024-01780},
pages = {101700},
year = {2024},
note = {2024 Sep 17;5(9):101700},
abstract = {Atypical teratoid/rhabdoid tumors (ATRTs) are highly
malignant embryonal tumors of the central nervous system
with a dismal prognosis. Using a newly developed and
validated patient-derived ATRT culture and xenograft model,
alongside a panel of primary ATRT models, we found that
ATRTs are selectively sensitive to the nucleoside analog
gemcitabine. Gene expression and protein analyses indicate
that gemcitabine treatment causes the degradation of sirtuin
1 (SIRT1), resulting in cell death through activation of
nuclear factor κB (NF-κB) and p53. Furthermore, we
discovered that gemcitabine-induced loss of SIRT1 results in
a nucleus-to-cytoplasm translocation of the sonic hedgehog
(SHH) signaling activator GLI2, explaining the observed
additional gemcitabine sensitivity in SHH-subtype ATRT.
Treatment of ATRT xenograft-bearing mice with gemcitabine
resulted in a $>30\%$ increase in median survival and
yielded long-term survivors in two independent
patient-derived xenograft models. These findings demonstrate
that ATRTs are highly sensitive to gemcitabine treatment and
may form part of a future multimodal treatment strategy for
ATRTs.},
keywords = {ATRT (Other) / atypical teratoid/rhabdoid tumor (Other) /
gemcitabine (Other) / neuro oncology (Other) / p53 (Other) /
patient-derived models (Other) / pediatric oncology (Other)
/ sirtuin 1 (Other) / therapy development (Other)},
cin = {B062 / HD01},
ddc = {610},
cid = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331},
pnm = {312 - Funktionelle und strukturelle Genomforschung
(POF4-312)},
pid = {G:(DE-HGF)POF4-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39208799},
doi = {10.1016/j.xcrm.2024.101700},
url = {https://inrepo02.dkfz.de/record/292537},
}