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Combination of Talazoparib and Palbociclib as a Potent Treatment Strategy in Bladder Cancer
The use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors represents a potent strategy for cancer therapy. Due to the complex molecular network that regulates cell cycle progression, cancer cells often acquire resistance mechanisms against these inhibitors. Previously, our group identified molecula...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145096/ https://www.ncbi.nlm.nih.gov/pubmed/33923231 http://dx.doi.org/10.3390/jpm11050340 |
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author | Klein, Florian G. Granier, Charlène Zhao, Yuling Pan, Qi Tong, Zhichao Gschwend, Jürgen E. Holm, Per Sonne Nawroth, Roman |
author_facet | Klein, Florian G. Granier, Charlène Zhao, Yuling Pan, Qi Tong, Zhichao Gschwend, Jürgen E. Holm, Per Sonne Nawroth, Roman |
author_sort | Klein, Florian G. |
collection | PubMed |
description | The use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors represents a potent strategy for cancer therapy. Due to the complex molecular network that regulates cell cycle progression, cancer cells often acquire resistance mechanisms against these inhibitors. Previously, our group identified molecular factors conferring resistance to CDK4/6 inhibition in bladder cancer (BLCA) that also included components within the DNA repair pathway. In this study, we validated whether a combinatory treatment approach of the CDK4/6 inhibitor Palbociclib with Poly-(ADP-Ribose) Polymerase (PARP) inhibitors improves therapy response in BLCA. First, a comparison of PARP inhibitors Talazoparib and Olaparib showed superior efficacy of Talazoparib in vitro and displayed high antitumor activity in xenografts in the chicken chorioallantoic membrane (CAM) model. Moreover, the combination of Talazoparib and the CDK4/6 inhibitor Palbociclib synergistically reduced tumor growth in Retinoblastoma protein (RB)-positive BLCA in vitro and in a CAM model, an effect that relies on Palbociclib-induced cell cycle arrest in G0/G1-phase complemented by a G2 arrest induced by Talazoparib. Interestingly, Talazoparib-induced apoptosis was reduced by Palbociclib. The combination of Palbociclib and Talazoparib effectively enhances BLCA therapy, and RB is a molecular biomarker of response to this treatment regimen. |
format | Online Article Text |
id | pubmed-8145096 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-81450962021-05-26 Combination of Talazoparib and Palbociclib as a Potent Treatment Strategy in Bladder Cancer Klein, Florian G. Granier, Charlène Zhao, Yuling Pan, Qi Tong, Zhichao Gschwend, Jürgen E. Holm, Per Sonne Nawroth, Roman J Pers Med Article The use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors represents a potent strategy for cancer therapy. Due to the complex molecular network that regulates cell cycle progression, cancer cells often acquire resistance mechanisms against these inhibitors. Previously, our group identified molecular factors conferring resistance to CDK4/6 inhibition in bladder cancer (BLCA) that also included components within the DNA repair pathway. In this study, we validated whether a combinatory treatment approach of the CDK4/6 inhibitor Palbociclib with Poly-(ADP-Ribose) Polymerase (PARP) inhibitors improves therapy response in BLCA. First, a comparison of PARP inhibitors Talazoparib and Olaparib showed superior efficacy of Talazoparib in vitro and displayed high antitumor activity in xenografts in the chicken chorioallantoic membrane (CAM) model. Moreover, the combination of Talazoparib and the CDK4/6 inhibitor Palbociclib synergistically reduced tumor growth in Retinoblastoma protein (RB)-positive BLCA in vitro and in a CAM model, an effect that relies on Palbociclib-induced cell cycle arrest in G0/G1-phase complemented by a G2 arrest induced by Talazoparib. Interestingly, Talazoparib-induced apoptosis was reduced by Palbociclib. The combination of Palbociclib and Talazoparib effectively enhances BLCA therapy, and RB is a molecular biomarker of response to this treatment regimen. MDPI 2021-04-24 /pmc/articles/PMC8145096/ /pubmed/33923231 http://dx.doi.org/10.3390/jpm11050340 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Klein, Florian G. Granier, Charlène Zhao, Yuling Pan, Qi Tong, Zhichao Gschwend, Jürgen E. Holm, Per Sonne Nawroth, Roman Combination of Talazoparib and Palbociclib as a Potent Treatment Strategy in Bladder Cancer |
title | Combination of Talazoparib and Palbociclib as a Potent Treatment Strategy in Bladder Cancer |
title_full | Combination of Talazoparib and Palbociclib as a Potent Treatment Strategy in Bladder Cancer |
title_fullStr | Combination of Talazoparib and Palbociclib as a Potent Treatment Strategy in Bladder Cancer |
title_full_unstemmed | Combination of Talazoparib and Palbociclib as a Potent Treatment Strategy in Bladder Cancer |
title_short | Combination of Talazoparib and Palbociclib as a Potent Treatment Strategy in Bladder Cancer |
title_sort | combination of talazoparib and palbociclib as a potent treatment strategy in bladder cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145096/ https://www.ncbi.nlm.nih.gov/pubmed/33923231 http://dx.doi.org/10.3390/jpm11050340 |
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