Details

Autor(en) / Beteiligte

• Han, Wanting
• Liu, Mingyu
• Han, Dong
• Toure, Anthia A.
• Li, Muqing
• Besschetnova, Anna
• Wang, Zifeng
• Patalano, Susan
• Macoska, Jill A.
• Lam, Hung-Ming
• Corey, Eva
• He, Housheng Hansen
• Gao, Shuai
• Balk, Steven P.
• Cai, Changmeng

Titel

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

Ist Teil von

• Molecular therapy, 2022-04, Vol.30 (4), p.1628-1644

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] We show that Rb family proteins play a central role in maintaining the global chromatin binding and transcriptional repression program of AR in prostate cancer cells and that the high-dose-androgen-induced transcriptional repression activity can be fully exploited by CDK4/6 inhibitor treatment, which blocks the hyperphosphorylation of Rb proteins.