TY  - JOUR
AU  - Heidler, Christopher L
AU  - Roth, Eva K
AU  - Thiemann, Markus
AU  - Blattmann, Claudia
AU  - Lopez Perez, Ramon
AU  - Huber, Peter E
AU  - Kovac, Michal
AU  - Amthor, Beate
AU  - Neu-Yilik, Gabriele
AU  - Kulozik, Andreas E
TI  - Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient-derived osteosarcoma cells and synergizes with cisplatin and talazoparib.
JO  - International journal of cancer
VL  - 147
IS  - 4
SN  - 1097-0215
CY  - Bognor Regis
PB  - Wiley-Liss
M1  - DKFZ-2019-02849
SP  - 1059-1070
PY  - 2020
N1  - 2020 Aug 15;147(4):1059-1070
AB  - Progress in the systemic control of osteosarcoma has been limited over the past decades thus indicating the urgent clinical need for the development of novel treatment strategies. Therefore, we have recently developed new preclinical models to study promising novel agents for the treatment of pediatric osteosarcoma. The checkpoint kinase (chk) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have recently been shown to be active in adult and pediatric malignancies, including sarcoma. We have now tested the potency of prexasertib in clonogenic survival assays in two new lines of primary patient-derived osteosarcoma cells and in two established osteosarcoma cell lines as a single agent and in combination with cisplatin and the poly ADP-ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double-stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations. In combination with cisplatin and talazoparib, prexasertib acts in a synergistic fashion. Chk1 inhibition by prexasertib and its combination with the DNA damaging agent cisplatin and the PARP-inhibitor talazoparib thus emerges as a potential new treatment option for pediatric osteosarcoma which will now have to be tested in preclinical primary patient derived in vivo models and clinical studies. This article is protected by copyright. All rights reserved.
LB  - PUB:(DE-HGF)16
C6  - pmid:31782150
DO  - DOI:10.1002/ijc.32814
UR  - https://inrepo02.dkfz.de/record/148283
ER  -