Exploiting the tumor-suppressive activity of the androgen receptor by CDK4/6 inhibition in castration-resistant prostate cancer.

Abstract

The androgen receptor (AR) plays a pivotal role in driving prostate cancer (PCa) development. However, when stimulated by high levels of androgens, AR can also function as a tumor suppressor in PCa cells. While the high-dose testosterone (high-T) treatment is currently being tested in clinical trials of castration-resistant prostate cancer (CRPC), there is still a pressing need to fully understand the underlying mechanism and thus develop treatment strategies to exploit this tumor-suppressive activity of AR. In this study, we demonstrate that retinoblastoma (Rb) family proteins play a central role in maintaining the global chromatin binding and transcriptional repression program of AR and that Rb inactivation desensitizes CRPC to the high-dose testosterone treatment in vitro and in vivo. Using a series of patient-derived xenograft (PDX) CRPC models, we further show that the efficacy of high-T treatment can be fully exploited by a CDK4/6 inhibitor, which strengthens the chromatin binding of the Rb-E2F repressor complex by blocking the hyperphosphorylation of Rb proteins. Overall, our study provides strong mechanistic and preclinical evidence on further developing clinical trials to combine high-T with CDK4/6 inhibitors in treating CRPC.

• Authors: Wanting Han, Mingyu Liu, Dong Han, Anthia A Toure, Muqing Li, Anna Besschetnova, Zifeng Wang, Susan Patalano, Jill A Macoska, Hung-Ming Lam, Eva Corey, Housheng Hansen He, Shuai Gao, Steven P Balk, Changmeng Cai
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 30 Issue 4 Pg. 1628-1644 (04 06 2022) ISSN: 1525-0024 [Electronic] United States
• PMID: 35121110 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Chromatin
• Receptors, Androgen
• Retinoblastoma Protein
• Testosterone
• CDK4 protein, human
• CDK6 protein, human
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6

Topics

• Cell Line, Tumor
• Chromatin
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors, therapeutic use)
• Cyclin-Dependent Kinase 6 (antagonists & inhibitors, therapeutic use)
• Genes, Tumor Suppressor
• Humans
• Male
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)
• Receptors, Androgen (genetics, metabolism)
• Retinoblastoma Protein (genetics)
• Testosterone (therapeutic use)