Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/82654
Citations | ||
Scopus | Web of Science® | Altmetric |
---|---|---|
?
|
?
|
Type: | Journal article |
Title: | Targeting cell cycle and hormone receptor pathways in cancer |
Author: | Comstock, C. Augello, M. Goodwin, J. de Leeuw, R. Schiewer, M. Ostrander, W. Burkhart, R. McClendon, A. McCue, P. Trabulsi, E. Lallas, C. Gomella, L. Centenera, M. Brody, J. Butler, L. Tilley, W. Knudsen, K. |
Citation: | Oncogene, 2013; 32(48):5481-5491 |
Publisher: | Nature Publishing Group |
Issue Date: | 2013 |
ISSN: | 0950-9232 1476-5594 |
Statement of Responsibility: | C E S Comstock, M A Augello, J F Goodwin, R de Leeuw, M J Schiewer, W F Ostrander Jr, R A Burkhart, A K McClendon, P A McCue, E J Trabulsi, C D Lallas, L G Gomella, M M Centenera, J R Brody, L M Butler, W D Tilley and K E Knudsen |
Abstract: | The cyclin/cyclin-dependent kinase (CDK)/retinoblastoma (RB)-axis is a critical modulator of cell cycle entry and is aberrant in many human cancers. New nodes of therapeutic intervention are needed that can delay or combat the onset of malignancies. The antitumor properties and mechanistic functions of PD-0332991 (PD; a potent and selective CDK4/6 inhibitor) were investigated using human prostate cancer (PCa) models and primary tumors. PD significantly impaired the capacity of PCa cells to proliferate by promoting a robust G1-arrest. Accordingly, key regulators of the G1-S cell cycle transition were modulated including G1 cyclins D, E and A. Subsequent investigation demonstrated the ability of PD to function in the presence of existing hormone-based regimens and to cooperate with ionizing radiation to further suppress cellular growth. Importantly, it was determined that PD is a critical mediator of PD action. The anti-proliferative impact of CDK4/6 inhibition was revealed through reduced proliferation and delayed growth using PCa cell xenografts. Finally, first-in-field effects of PD on proliferation were observed in primary human prostatectomy tumor tissue explants. This study shows that selective CDK4/6 inhibition, using PD either as a single-agent or in combination, hinders key proliferative pathways necessary for disease progression and that RB status is a critical prognostic determinant for therapeutic efficacy. Combined, these pre-clinical findings identify selective targeting of CDK4/6 as a bona fide therapeutic target in both early stage and advanced PCa and underscore the benefit of personalized medicine to enhance treatment response. |
Keywords: | PD-0332991 cyclin-dependent kinase retinoblastoma protein prostate cancer tumor explants |
Rights: | © 2013 Macmillan Publishers Limited. All Rights Reserved. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/. |
DOI: | 10.1038/onc.2013.83 |
Published version: | http://dx.doi.org/10.1038/onc.2013.83 |
Appears in Collections: | Aurora harvest 4 Medicine publications |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
hdl_82654.pdf | Published version | 2.57 MB | Adobe PDF | View/Open |
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.