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Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient‐derived osteosarcoma cells and synergizes with cisplatin and talazoparib

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 pediat...

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Autores principales: Heidler, Christopher L., Roth, Eva K., Thiemann, Markus, Blattmann, Claudia, Perez, Ramon L., Huber, Peter E., Kovac, Michal, Amthor, Beate, Neu‐Yilik, Gabriele, Kulozik, Andreas E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384073/
https://www.ncbi.nlm.nih.gov/pubmed/31782150
http://dx.doi.org/10.1002/ijc.32814
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author Heidler, Christopher L.
Roth, Eva K.
Thiemann, Markus
Blattmann, Claudia
Perez, Ramon L.
Huber, Peter E.
Kovac, Michal
Amthor, Beate
Neu‐Yilik, Gabriele
Kulozik, Andreas E.
author_facet Heidler, Christopher L.
Roth, Eva K.
Thiemann, Markus
Blattmann, Claudia
Perez, Ramon L.
Huber, Peter E.
Kovac, Michal
Amthor, Beate
Neu‐Yilik, Gabriele
Kulozik, Andreas E.
author_sort Heidler, Christopher L.
collection PubMed
description 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.
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spelling pubmed-73840732020-07-28 Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient‐derived osteosarcoma cells and synergizes with cisplatin and talazoparib Heidler, Christopher L. Roth, Eva K. Thiemann, Markus Blattmann, Claudia Perez, Ramon L. Huber, Peter E. Kovac, Michal Amthor, Beate Neu‐Yilik, Gabriele Kulozik, Andreas E. Int J Cancer Cancer Therapy and Prevention 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. John Wiley & Sons, Inc. 2019-12-19 2020-08-15 /pmc/articles/PMC7384073/ /pubmed/31782150 http://dx.doi.org/10.1002/ijc.32814 Text en © 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Cancer Therapy and Prevention
Heidler, Christopher L.
Roth, Eva K.
Thiemann, Markus
Blattmann, Claudia
Perez, Ramon L.
Huber, Peter E.
Kovac, Michal
Amthor, Beate
Neu‐Yilik, Gabriele
Kulozik, Andreas E.
Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient‐derived osteosarcoma cells and synergizes with cisplatin and talazoparib
title Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient‐derived osteosarcoma cells and synergizes with cisplatin and talazoparib
title_full Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient‐derived osteosarcoma cells and synergizes with cisplatin and talazoparib
title_fullStr Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient‐derived osteosarcoma cells and synergizes with cisplatin and talazoparib
title_full_unstemmed Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient‐derived osteosarcoma cells and synergizes with cisplatin and talazoparib
title_short Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient‐derived osteosarcoma cells and synergizes with cisplatin and talazoparib
title_sort prexasertib (ly2606368) reduces clonogenic survival by inducing apoptosis in primary patient‐derived osteosarcoma cells and synergizes with cisplatin and talazoparib
topic Cancer Therapy and Prevention
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384073/
https://www.ncbi.nlm.nih.gov/pubmed/31782150
http://dx.doi.org/10.1002/ijc.32814
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