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Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas

PURPOSE: MDM2 and CDK4 are frequently co-amplified in well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS). We aimed to determine whether combined MDM2/CDK4 targeting is associated with higher antitumour activity than a single agent in preclinical models of DDLPS. EXPERIMENTAL DESIGN: DDLP...

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Autores principales: Laroche-Clary, Audrey, Chaire, Vanessa, Algeo, Marie-Paule, Derieppe, Marie-Alix, Loarer, François L., Italiano, Antoine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477309/
https://www.ncbi.nlm.nih.gov/pubmed/28629371
http://dx.doi.org/10.1186/s13045-017-0482-3
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author Laroche-Clary, Audrey
Chaire, Vanessa
Algeo, Marie-Paule
Derieppe, Marie-Alix
Loarer, François L.
Italiano, Antoine
author_facet Laroche-Clary, Audrey
Chaire, Vanessa
Algeo, Marie-Paule
Derieppe, Marie-Alix
Loarer, François L.
Italiano, Antoine
author_sort Laroche-Clary, Audrey
collection PubMed
description PURPOSE: MDM2 and CDK4 are frequently co-amplified in well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS). We aimed to determine whether combined MDM2/CDK4 targeting is associated with higher antitumour activity than a single agent in preclinical models of DDLPS. EXPERIMENTAL DESIGN: DDLPS cells were exposed to RG7388 (MDM2 antagonist) and palbociclib (CDK4 inhibitor), and apoptosis and signalling/survival pathway perturbations were monitored by flow cytometry and Western blotting. Xenograft mouse models were used to assess tumour growth and survival. Treatment efficacy was assessed by Western blotting, histopathology and tumour volume. RESULTS: RG7388 and palbociclib together exerted a greater antitumour effect than either drug alone, with significant differences in cell viability after a 72-h treatment with RG7388 and/or palbociclib. The combination treatment significantly increased apoptosis compared to the single agents. We then analysed the in vivo antitumour activity of RG7388 and palbociclib in a xenograft model of DDLPS. The combination regimen reduced the tumour growth rate compared with a single agent alone and significantly increased the median progression-free survival. CONCLUSIONS: Our results provide a strong rationale for evaluating the therapeutic potential of CDK4 inhibitors as potentiators of MDM2 antagonists in DDLPS and justify clinical trials in this setting.
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spelling pubmed-54773092017-06-23 Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas Laroche-Clary, Audrey Chaire, Vanessa Algeo, Marie-Paule Derieppe, Marie-Alix Loarer, François L. Italiano, Antoine J Hematol Oncol Rapid Communication PURPOSE: MDM2 and CDK4 are frequently co-amplified in well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS). We aimed to determine whether combined MDM2/CDK4 targeting is associated with higher antitumour activity than a single agent in preclinical models of DDLPS. EXPERIMENTAL DESIGN: DDLPS cells were exposed to RG7388 (MDM2 antagonist) and palbociclib (CDK4 inhibitor), and apoptosis and signalling/survival pathway perturbations were monitored by flow cytometry and Western blotting. Xenograft mouse models were used to assess tumour growth and survival. Treatment efficacy was assessed by Western blotting, histopathology and tumour volume. RESULTS: RG7388 and palbociclib together exerted a greater antitumour effect than either drug alone, with significant differences in cell viability after a 72-h treatment with RG7388 and/or palbociclib. The combination treatment significantly increased apoptosis compared to the single agents. We then analysed the in vivo antitumour activity of RG7388 and palbociclib in a xenograft model of DDLPS. The combination regimen reduced the tumour growth rate compared with a single agent alone and significantly increased the median progression-free survival. CONCLUSIONS: Our results provide a strong rationale for evaluating the therapeutic potential of CDK4 inhibitors as potentiators of MDM2 antagonists in DDLPS and justify clinical trials in this setting. BioMed Central 2017-06-19 /pmc/articles/PMC5477309/ /pubmed/28629371 http://dx.doi.org/10.1186/s13045-017-0482-3 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Rapid Communication
Laroche-Clary, Audrey
Chaire, Vanessa
Algeo, Marie-Paule
Derieppe, Marie-Alix
Loarer, François L.
Italiano, Antoine
Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas
title Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas
title_full Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas
title_fullStr Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas
title_full_unstemmed Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas
title_short Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas
title_sort combined targeting of mdm2 and cdk4 is synergistic in dedifferentiated liposarcomas
topic Rapid Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477309/
https://www.ncbi.nlm.nih.gov/pubmed/28629371
http://dx.doi.org/10.1186/s13045-017-0482-3
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