title: Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias.
abstract: 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. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.|Centro de Investigación Biomédica en Red de Oncología (CIBERONC), Madrid, Spain.
authors.forename: Maria Alba
authors.initials: MA
authors.lastname: Dosil
authors.affiliation: Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Mirantes
authors.affiliation: Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.|Centro de Investigación Biomédica en Red de Oncología (CIBERONC), Madrid, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Eritja
authors.affiliation: Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Isidre
authors.initials: I
authors.lastname: Felip
authors.affiliation: Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: Navaridas
authors.affiliation: Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.|Centro de Investigación Biomédica en Red de Oncología (CIBERONC), Madrid, Spain.
authors.forename: Sònia
authors.initials: S
authors.lastname: Gatius
authors.affiliation: Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.|Centro de Investigación Biomédica en Red de Oncología (CIBERONC), Madrid, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Santacana
authors.affiliation: Biomedical Research Group in Gynaecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Colàs
authors.affiliation: Biomedical Research Group in Gynaecology, Vall Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Cristian
authors.initials: C
authors.lastname: Moiola
authors.affiliation: Department of Pharmacology, Hospital Universitari Arnau de Vilanova. Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Joan Antoni
authors.initials: JA
authors.lastname: Schoenenberger
authors.affiliation: Departament de Medicina Experimental, Universitat de Lleida, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Encinas
authors.affiliation: Cell Cycle Group, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Eloi
authors.initials: E
authors.lastname: Garí
authors.affiliation: Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.|Centro de Investigación Biomédica en Red de Oncología (CIBERONC), Madrid, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
authors.affiliation: Oncologic Pathology Group, Departament de Ciències Mèdiques Bàsiques, Universitat de Lleida, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomèdica de Lleida, IRBLleida, Lleida, Spain.|Centro de Investigación Biomédica en Red de Oncología (CIBERONC), Madrid, Spain.
authors.forename: Xavier
authors.identifier: 0000-0003-1921-0449
authors.initials: X
authors.lastname: Dolcet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D063646:Carcinogenesis; D019938:Cyclin D1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000235:genetics; D004195:Disease Models, Animal; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D013629:Tamoxifen / Q000009:adverse effects; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; C530104:CCND1 protein, human; C530105:Ccnd1 protein, mouse; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D013629:Tamoxifen; D019938:Cyclin D1; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C500026:palbociclib
keywords: CDK4/6; PTEN; cyclin D1; endometrial carcinoma; palbociclib