Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias

Dosil Garcia, Maria Alba; Mirantes Barbeito, Cristina; Eritja Sánchez, Núria; Felip, Isidre; Navaridas Fernández de Bobadilla, Raúl; Gatius Calderó, Sònia; Santacana Espasa, Maria; Colàs, Eva; Moiola, Cristian P.; Schoenenberger, Joan Antoni; Encinas Martín, Mario; Garí Marsol, Eloi; Matias-Guiu, Xavier; Dolcet Roca, Xavier

doi:https://doi.org/10.1002/path.4896

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Issue date

2017-04-28

Author

Dosil Garcia, Maria Alba

Mirantes Barbeito, Cristina

Eritja Sánchez, Núria

Felip, Isidre

Navaridas Fernández de Bobadilla, Raúl

Gatius Calderó, Sònia

Santacana Espasa, Maria

Colàs, Eva

Moiola, Cristian P.

Schoenenberger, Joan Antoni

Encinas Martín, Mario

Garí Marsol, Eloi

Matias-Guiu, Xavier

Dolcet Roca, Xavier

Suggested citation

Dosil Garcia, Maria Alba; Mirantes Barbeito, Cristina; Eritja Sánchez, Núria; Felip, Isidre; Navaridas Fernández de Bobadilla, Raúl; Gatius Calderó, Sònia; ... Dolcet Roca, Xavier. (2017) . Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias. Journal of Pathology, 2017, vol. 242, núm. 2, p. 152-164. https://doi.org/10.1002/path.4896.

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.

URI

http://hdl.handle.net/10459.1/63495

DOI

https://doi.org/10.1002/path.4896

Is part of

Journal of Pathology, 2017, vol. 242, núm. 2, p. 152-164