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.

Modeling Endometrial Cancer: Past, Present, and Future

“…Different Akt and mTOR inhibitors have been tested in transgenic mice, showing good responses [106,109]. Recent preclinical studies using transgenic EC mice tested olaparib (PARP-inhibitor) [107], dienogest (fourth-generation progestin) [117], and palbociclib (CDK4,6 inhibitor) [118]. Such models have also been used to evaluate the effect of diet on EC tumorigenesis, showing that the elevation of ω-3-polyunsaturated fatty acids attenuates PTEN deficiency-induced EC development [119].…”

Patient-Derived Xenograft Models for Endometrial Cancer Research

“…In EC, Dosil et al [60] performed the first preclinical study to test the therapeutic potential of palbociclib; specifically, this was tested in the endometrial malignancies driven by Pten deficiency. This work started with the assessment of palbociclib response in vitro and in a PTEN-deficient GEM model and was finally validated in a PTEN-mutated PDX model of endometrioid EC of FIGO stage IIIC and grade 2.…”

“…This work started with the assessment of palbociclib response in vitro and in a PTEN-deficient GEM model and was finally validated in a PTEN-mutated PDX model of endometrioid EC of FIGO stage IIIC and grade 2. This work evidenced that palbociclib has therapeutic potential as an anticancer drug in the endometrium, since it reduces tumour cell proliferation and disrupts the tumourigenesis process [60]. …”

Cell Cycle Control by PTEN

“…The enhanced understanding of PTEN function in controlling progression through the first gap phase (G1) of the cell cycle has implications for cancer treatment. For example, based on the prevailing upregulation of cyclin D1 following PTEN loss, a recent preclinical study demonstrated a significant therapeutic effect of cyclin D1-Cdk4/6 inhibition in a Pten -deficient endometrial tumor model [70]. In summary, PTEN inhibits the G1-S transition to prevent premature progression to DNA replication and resultant CIN.…”