TY  - JOUR
AU  - Khalid, Umar
AU  - Simovic, Milena
AU  - Hammann, Linda A
AU  - Iskar, Murat
AU  - Wong, John K L
AU  - Kumar, Rithu
AU  - Jugold, Manfred
AU  - Sill, Martin
AU  - Bolkestein, Michiel
AU  - Kolb, Thorsten
AU  - Hergt, Michaela
AU  - Devens, Frauke
AU  - Ecker, Jonas
AU  - Kool, Marcel
AU  - Milde, Till
AU  - Westermann, Frank
AU  - Benner, Axel
AU  - Lewis, Joe
AU  - Dietrich, Sascha
AU  - Pfister, Stefan M
AU  - Lichter, Peter
AU  - Zapatka, Marc
AU  - Ernst, Aurélie
TI  - A synergistic interaction between HDAC- and PARP inhibitors in childhood tumors with chromothripsis.
JO  - International journal of cancer
VL  - 151
IS  - 4
SN  - 0020-7136
CY  - Bognor Regis
PB  - Wiley-Liss
M1  - DKFZ-2022-00958
SP  - 590-606
PY  - 2022
N1  - #EA:B420#LA:B420# / 2022 Aug 15;151(4):590-606
AB  - Chromothripsis is a form of genomic instability characterized by the occurrence of tens to hundreds of clustered DNA double-strand breaks in a one-off catastrophic event. Rearrangements associated with chromothripsis are detectable in numerous tumor entities and linked with poor prognosis in some of these, such as Sonic Hedgehog medulloblastoma, neuroblastoma and osteosarcoma. Hence, there is a need for therapeutic strategies eliminating tumor cells with chromothripsis. Defects in DNA double-strand break repair, and in particular homologous recombination repair, have been linked with chromothripsis. Targeting DNA repair deficiencies by synthetic lethality approaches, we performed a synergy screen using drug libraries (n = 375 compounds, 15 models) combined with either a PARP inhibitor or cisplatin. This revealed a synergistic interaction between the HDAC inhibitor romidepsin and PARP inhibition. Functional assays, transcriptome analyses and in vivo validation in patient-derived xenograft mouse models confirmed the efficacy of the combinatorial treatment.
KW  - HDAC inhibitor (Other)
KW  - PARP inhibitor (Other)
KW  - chromothripsis (Other)
KW  - synergy (Other)
KW  - synthetic lethality (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:35411591
DO  - DOI:10.1002/ijc.34027
UR  - https://inrepo02.dkfz.de/record/179901
ER  -