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@ARTICLE{Alimova:181116,
author = {I. Alimova and A. M. Pierce and P. Harris and A. Donson and
D. K. Birks and E. Prince and I. Balakrishnan and N. K.
Foreman and M. Kool$^*$ and L. Hoffman and S. Venkataraman
and R. Vibhakar},
title = {{T}argeting {P}olo-like kinase 1 in {SMARCB}1 deleted
atypical teratoid rhabdoid tumor.},
journal = {OncoTarget},
volume = {8},
number = {57},
issn = {1949-2553},
address = {[S.l.]},
publisher = {Impact Journals LLC},
reportid = {DKFZ-2022-01785},
pages = {97290 - 97303},
year = {2017},
abstract = {Atypical teratoid rhabdoid tumor (ATRT) is an aggressive
and malignant pediatric brain tumor. Polo-like kinase 1
(PLK1) is highly expressed in many cancers and essential for
mitosis. Overexpression of PLK1 promotes chromosome
instability and aneuploidy by overriding the G2-M DNA damage
and spindle checkpoints. Recent studies suggest that
targeting PLK1 by small molecule inhibitors is a promising
approach to tumor therapy. We investigated the effect of
PLK1 inhibition in ATRT. Gene expression analysis showed
that PLK1 was overexpressed in ATRT patient samples and
tumor cell lines. Genetic inhibition of PLK1 with shRNA
potently suppressed ATRT cell growth in vitro. Treatment
with the PLK1 inhibitor BI 6727 (Volasertib) significantly
decreased cell growth, inhibited clonogenic potential, and
induced apoptosis. BI6727 treatment led to G2-M phase
arrest, consistent with PLK1's role as a critical regulator
of mitosis. Moreover, inhibition of PLK1 by BI6727
suppressed the tumor-sphere formation of ATRT cells.
Treatment also significantly decreased levels of the DNA
damage proteins Ku80 and RAD51 and increased γ-H2AX
expression, indicating that BI 6727 can induce DNA damage.
Importantly, BI6727 significantly enhanced radiation
sensitivity of ATRT cells. In vivo, BI6727 slowed growth of
ATRT tumors and prolonged survival in a xenograft model.
PLK1 inhibition is a compelling new therapeutic approach for
treating ATRT, and the use of BI6727 should be evaluated in
clinical studies.},
keywords = {ATRT (Other) / Polo-like kinase 1 (Other) / SMARCB1 (Other)
/ volasertib (Other)},
cin = {B062},
ddc = {610},
cid = {I:(DE-He78)B062-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29228610},
pmc = {pmc:PMC5722562},
doi = {10.18632/oncotarget.21932},
url = {https://inrepo02.dkfz.de/record/181116},
}