Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias

PTEN is one of the most frequently mutated genes in human cancers. The frequency of PTEN alterations is particularly high in endometrial carcinomas. Loss of PTEN leads to dysregulation of cell division, and promotes the accumulation of cell cycle complexes such as cyclin D1-CDK4/6, which is an impor...

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Authors: Dosil Garcia, Maria Alba, Mirantes Barbeito, Cristina, Eritja Sánchez, Núria, Felip Nogués, Isidre, Navaridas Fernández de Bobadilla, Raúl, Gatius Calderó, Sònia, Santacana Espasa, Maria, Colás, Eva, Moiola, Cristian P., Schoenenberger, Joan Antoni, Encinas Martín, Mario, Garí Marsol, Eloi, Matias-Guiu, Xavier, Dolcet Roca, Xavier
Format: article
Status:Versión aceptada para publicación
Publication Date:2017
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10459.1/63495
Online Access:https://doi.org/10.1002/path.4896
http://hdl.handle.net/10459.1/63495
Access Level:Open access
Keyword:Endometrial carcinoma
Palbociclib
PTEN
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spelling Palbociclib has antitumour effects on Pten-deficient endometrial neoplasiasInhibition of Cyclin D-CDK4/6 axis in PTEN-deficient neoplasiasDosil Garcia, Maria AlbaMirantes Barbeito, CristinaEritja Sánchez, NúriaFelip Nogués, IsidreNavaridas Fernández de Bobadilla, RaúlGatius Calderó, SòniaSantacana Espasa, MariaColás, EvaMoiola, Cristian P.Schoenenberger, Joan AntoniEncinas Martín, MarioGarí Marsol, EloiMatias-Guiu, XavierDolcet Roca, XavierEndometrial carcinomaPalbociclibPTENPTEN is one of the most frequently mutated genes in human cancers. The frequency of PTEN alterations is particularly high in endometrial carcinomas. Loss of PTEN leads to dysregulation of cell division, and promotes the accumulation of cell cycle complexes such as cyclin D1-CDK4/6, which is an important feature of the tumour phenotype. Cell cycle proteins have been presented as key targets in the treatment of the pathogenesis of cancer, and several CDK inhibitors have been developed as a strategy to generate new anticancer drugs. Palbociclib (PD-332991) specifically inhibits CDK4/6, and it has been approved for use in metastatic breast cancer in combination with letrazole. Here, we used a tamoxifen-inducible Pten knockout mouse model to assess the antitumour effects of cyclin D1 knockout and CDK4/6 inhibition by palbociclib on endometrial tumours. Interestingly, both cyclin D1 deficiency and palbociclib treatment triggered shrinkage of endometrial neoplasias. In addition, palbociclib treatment significantly increased the survival of Pten-deficient mice, and, as expected, had a general effect in reducing tumour cell proliferation. To further analyse the effects of palbociclib on endometrial carcinoma, we established subcutaneous tumours with human endometrial cancer cell lines and primary endometrial cancer xenografts, which allowed us to provide more translational and predictive data. To date, this is the first preclinical study evaluating the response to CDK4/6 inhibition in endometrial malignancies driven by PTEN deficiency, and it reveals an important role of cyclin D-CDK4/6 activity in their development.This work was supported by grants FIS PI13/00263, SAF2016-80157-R, PI13/01701, 2009SGR794,Grupos estables AECC (AECC2011), RETICS(RD12/0036/0013), Catalunya contra el cáncer, Programa de intensificación de la investigación, Instituto Carlos III, and BFU 2013-42895-P. MAD holds a predoctoral fellowship from Ministerio de EducaciónWiley2018201820172018info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://doi.org/10.1002/path.4896http://hdl.handle.net/10459.1/63495http://hdl.handle.net/10459.1/63495reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/grantAgreement/MINECO//SAF2016-80157-Rinfo:eu-repo/grantAgreement/MINECO//BFU2013-42895-PVersió postprint del document publicat a: https://doi.org/10.1002/path.4896Journal of Pathology, 2017, vol. 242, núm. 2, p. 152-164(c) Pathological Society of Great Britain and Ireland, 2017info:eu-repo/semantics/openAccessoai:recercat.cat:10459.1/634952026-05-29T05:05:01Z
dc.title.none.fl_str_mv Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias
Inhibition of Cyclin D-CDK4/6 axis in PTEN-deficient neoplasias
title Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias
spellingShingle Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias
Dosil Garcia, Maria Alba
Endometrial carcinoma
Palbociclib
PTEN
title_short Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias
title_full Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias
title_fullStr Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias
title_full_unstemmed Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias
title_sort Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias
dc.creator.none.fl_str_mv Dosil Garcia, Maria Alba
Mirantes Barbeito, Cristina
Eritja Sánchez, Núria
Felip Nogués, Isidre
Navaridas Fernández de Bobadilla, Raúl
Gatius Calderó, Sònia
Santacana Espasa, Maria
Colás, Eva
Moiola, Cristian P.
Schoenenberger, Joan Antoni
Encinas Martín, Mario
Garí Marsol, Eloi
Matias-Guiu, Xavier
Dolcet Roca, Xavier
author Dosil Garcia, Maria Alba
author_facet Dosil Garcia, Maria Alba
Mirantes Barbeito, Cristina
Eritja Sánchez, Núria
Felip Nogués, Isidre
Navaridas Fernández de Bobadilla, Raúl
Gatius Calderó, Sònia
Santacana Espasa, Maria
Colás, Eva
Moiola, Cristian P.
Schoenenberger, Joan Antoni
Encinas Martín, Mario
Garí Marsol, Eloi
Matias-Guiu, Xavier
Dolcet Roca, Xavier
author_role author
author2 Mirantes Barbeito, Cristina
Eritja Sánchez, Núria
Felip Nogués, Isidre
Navaridas Fernández de Bobadilla, Raúl
Gatius Calderó, Sònia
Santacana Espasa, Maria
Colás, Eva
Moiola, Cristian P.
Schoenenberger, Joan Antoni
Encinas Martín, Mario
Garí Marsol, Eloi
Matias-Guiu, Xavier
Dolcet Roca, Xavier
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Endometrial carcinoma
Palbociclib
PTEN
topic Endometrial carcinoma
Palbociclib
PTEN
description PTEN is one of the most frequently mutated genes in human cancers. The frequency of PTEN alterations is particularly high in endometrial carcinomas. Loss of PTEN leads to dysregulation of cell division, and promotes the accumulation of cell cycle complexes such as cyclin D1-CDK4/6, which is an important feature of the tumour phenotype. Cell cycle proteins have been presented as key targets in the treatment of the pathogenesis of cancer, and several CDK inhibitors have been developed as a strategy to generate new anticancer drugs. Palbociclib (PD-332991) specifically inhibits CDK4/6, and it has been approved for use in metastatic breast cancer in combination with letrazole. Here, we used a tamoxifen-inducible Pten knockout mouse model to assess the antitumour effects of cyclin D1 knockout and CDK4/6 inhibition by palbociclib on endometrial tumours. Interestingly, both cyclin D1 deficiency and palbociclib treatment triggered shrinkage of endometrial neoplasias. In addition, palbociclib treatment significantly increased the survival of Pten-deficient mice, and, as expected, had a general effect in reducing tumour cell proliferation. To further analyse the effects of palbociclib on endometrial carcinoma, we established subcutaneous tumours with human endometrial cancer cell lines and primary endometrial cancer xenografts, which allowed us to provide more translational and predictive data. To date, this is the first preclinical study evaluating the response to CDK4/6 inhibition in endometrial malignancies driven by PTEN deficiency, and it reveals an important role of cyclin D-CDK4/6 activity in their development.
publishDate 2017
dc.date.none.fl_str_mv 2017
2018
2018
2018
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://doi.org/10.1002/path.4896
http://hdl.handle.net/10459.1/63495
http://hdl.handle.net/10459.1/63495
url https://doi.org/10.1002/path.4896
http://hdl.handle.net/10459.1/63495
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MINECO//SAF2016-80157-R
info:eu-repo/grantAgreement/MINECO//BFU2013-42895-P
Versió postprint del document publicat a: https://doi.org/10.1002/path.4896
Journal of Pathology, 2017, vol. 242, núm. 2, p. 152-164
dc.rights.none.fl_str_mv (c) Pathological Society of Great Britain and Ireland, 2017
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Pathological Society of Great Britain and Ireland, 2017
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Wiley
publisher.none.fl_str_mv Wiley
dc.source.none.fl_str_mv reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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