Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA

Sarcomas are malignant tumors accounting for a high percentage of cancer morbidity and mortality in children and young adults. Surgery and radiation therapy are the accepted treatments for most sarcomas; however, patients with metastatic disease are treated with systemic chemotherapy. Many tumors di...

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Autores: Pérez, Marco, Muñoz Galván, Sandra, Jiménez García, Manuel Pedro, Marín López, Juan José, Carnero Moya, Amancio
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2015
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:dnet:idus________::6a0273c8e326115c847863b77fcfb832
Acceso en línea:https://hdl.handle.net/11441/184482
https://doi.org/10.18632/oncotarget.5829
Access Level:acceso abierto
Palabra clave:Cell cycle
CDKs
Cyclin dependent kinase inhibitor
Sarcomas
Cellular senescence
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spelling Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNAPérez, MarcoMuñoz Galván, SandraJiménez García, Manuel PedroMarín López, Juan JoséCarnero Moya, AmancioCell cycleCDKsCyclin dependent kinase inhibitorSarcomasCellular senescenceSarcomas are malignant tumors accounting for a high percentage of cancer morbidity and mortality in children and young adults. Surgery and radiation therapy are the accepted treatments for most sarcomas; however, patients with metastatic disease are treated with systemic chemotherapy. Many tumors display marginal levels of chemoresponsiveness and new treatment approaches are needed. Deregulation of the G1 checkpoint is crucial for various oncogenic transformation processes, suggesting that many cancer cell types depend on CDK4/6 activity. Thus, CDK4/6 activity appears to represent a promising therapeutic target for cancer treatment. In the present work, we explore the efficacy of CDK4 inhibition using palbociclib (PD0332991), a highly selective inhibitor of CDK4/6, in a panel of sarcoma cell lines and sarcoma tumor xenografts (PDXs). Palbociclib induces senescence in these cell lines and the responsiveness of these cell lines correlated with their levels of CDK4 mRNA. Palbociclib is also active in vivo against sarcomas displaying high levels of CDK4 but not against sarcomas displaying low levels of CDK4 and high levels of p16ink4a. The analysis of tumors growing after palbociclib showed a clear decrease in the CDK4 levels, indicating that clonal selection occurred in these treated tumors. In summary, our data support the efficacy of CDK4 inhibitors against sarcomas displaying increased CDK4 levels, particularly fibrosarcomas and MPNST. Our results also suggest that high levels of p16ink4a may indicate poor efficacy of CDK4 inhibitors.Impact JournalsMedicina Preventiva y Salud PúblicaJunta de AndalucíaEuropean Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)Fundació Josep BotetInstituto de Salud Carlos IIIGobierno de España2015info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/184482https://doi.org/10.18632/oncotarget.5829reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésOncotarget, 6 (38), 40557-40574. CTS-6844CTS-1848PI-0135-2010PI-0306-2012PI12/00137PI15/00045Grant 13/0004RD12/0036/0017RD12/0036/0017https://www.oncotarget.com/article/5829/text/info:eu-repo/semantics/openAccessoai:dnet:idus________::6a0273c8e326115c847863b77fcfb8322026-06-17T12:51:07Z
dc.title.none.fl_str_mv Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA
title Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA
spellingShingle Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA
Pérez, Marco
Cell cycle
CDKs
Cyclin dependent kinase inhibitor
Sarcomas
Cellular senescence
title_short Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA
title_full Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA
title_fullStr Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA
title_full_unstemmed Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA
title_sort Efficacy of CDK4 inhibition against sarcomas depends on their levels of CDK4 and p16ink4 mRNA
dc.creator.none.fl_str_mv Pérez, Marco
Muñoz Galván, Sandra
Jiménez García, Manuel Pedro
Marín López, Juan José
Carnero Moya, Amancio
author Pérez, Marco
author_facet Pérez, Marco
Muñoz Galván, Sandra
Jiménez García, Manuel Pedro
Marín López, Juan José
Carnero Moya, Amancio
author_role author
author2 Muñoz Galván, Sandra
Jiménez García, Manuel Pedro
Marín López, Juan José
Carnero Moya, Amancio
author2_role author
author
author
author
dc.contributor.none.fl_str_mv Medicina Preventiva y Salud Pública
Junta de Andalucía
European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER)
Fundació Josep Botet
Instituto de Salud Carlos III
Gobierno de España
dc.subject.none.fl_str_mv Cell cycle
CDKs
Cyclin dependent kinase inhibitor
Sarcomas
Cellular senescence
topic Cell cycle
CDKs
Cyclin dependent kinase inhibitor
Sarcomas
Cellular senescence
description Sarcomas are malignant tumors accounting for a high percentage of cancer morbidity and mortality in children and young adults. Surgery and radiation therapy are the accepted treatments for most sarcomas; however, patients with metastatic disease are treated with systemic chemotherapy. Many tumors display marginal levels of chemoresponsiveness and new treatment approaches are needed. Deregulation of the G1 checkpoint is crucial for various oncogenic transformation processes, suggesting that many cancer cell types depend on CDK4/6 activity. Thus, CDK4/6 activity appears to represent a promising therapeutic target for cancer treatment. In the present work, we explore the efficacy of CDK4 inhibition using palbociclib (PD0332991), a highly selective inhibitor of CDK4/6, in a panel of sarcoma cell lines and sarcoma tumor xenografts (PDXs). Palbociclib induces senescence in these cell lines and the responsiveness of these cell lines correlated with their levels of CDK4 mRNA. Palbociclib is also active in vivo against sarcomas displaying high levels of CDK4 but not against sarcomas displaying low levels of CDK4 and high levels of p16ink4a. The analysis of tumors growing after palbociclib showed a clear decrease in the CDK4 levels, indicating that clonal selection occurred in these treated tumors. In summary, our data support the efficacy of CDK4 inhibitors against sarcomas displaying increased CDK4 levels, particularly fibrosarcomas and MPNST. Our results also suggest that high levels of p16ink4a may indicate poor efficacy of CDK4 inhibitors.
publishDate 2015
dc.date.none.fl_str_mv 2015
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/184482
https://doi.org/10.18632/oncotarget.5829
url https://hdl.handle.net/11441/184482
https://doi.org/10.18632/oncotarget.5829
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Oncotarget, 6 (38), 40557-40574.
CTS-6844
CTS-1848
PI-0135-2010
PI-0306-2012
PI12/00137
PI15/00045
Grant 13/0004
RD12/0036/0017
RD12/0036/0017
https://www.oncotarget.com/article/5829/text/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Impact Journals
publisher.none.fl_str_mv Impact Journals
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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