| Autor: |
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 |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Molecular therapy : the journal of the American Society of Gene Therapy. 30(4) |
| ISSN: |
1525-0024 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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