Combination of Talazoparib and Palbociclib as a Potent Treatment Strategy in Bladder Cancer

被引:10
|
作者
Klein, Florian G. [1 ]
Granier, Charlene [1 ]
Zhao, Yuling [1 ]
Pan, Qi [1 ,3 ]
Tong, Zhichao [1 ,4 ]
Gschwend, Jurgen E. [1 ]
Holm, Per Sonne [1 ,2 ]
Nawroth, Roman [1 ]
机构
[1] Tech Univ Munich, Dept Urol, Klinikum Rechts Isar, D-81675 Munich, Germany
[2] Med Univ Innsbruck, Dept Oral & Maxillofacial Surg, A-6020 Innsbruck, Austria
[3] Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Sch Med, Dept Urol, Shanghai 200240, Peoples R China
[4] Hosp Harbin Med Univ, Dept Urol, 23 Youzheng St, Harbin 150086, Peoples R China
来源
JOURNAL OF PERSONALIZED MEDICINE | 2021年 / 11卷 / 05期
关键词
bladder cancer; combination therapy; Talazoparib; Olaparib; Palbociclib; Retinoblastoma protein; apoptosis; chorioallantoic membrane model; CELL LUNG-CANCER; CDK4/6; INHIBITORS; DNA-DAMAGE; BREAST-CANCER; POLYMERASE INHIBITORS; CLINICAL DEVELOPMENT; CYCLIN D1; REPAIR; PARP; ACTIVATION;
D O I
10.3390/jpm11050340
中图分类号
R19 [保健组织与事业(卫生事业管理)];
学科分类号
摘要
The use of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors represents a potent strategy for cancer therapy. Due to the complex molecular network that regulates cell cycle progression, cancer cells often acquire resistance mechanisms against these inhibitors. Previously, our group identified molecular factors conferring resistance to CDK4/6 inhibition in bladder cancer (BLCA) that also included components within the DNA repair pathway. In this study, we validated whether a combinatory treatment approach of the CDK4/6 inhibitor Palbociclib with Poly-(ADP-Ribose) Polymerase (PARP) inhibitors improves therapy response in BLCA. First, a comparison of PARP inhibitors Talazoparib and Olaparib showed superior efficacy of Talazoparib in vitro and displayed high antitumor activity in xenografts in the chicken chorioallantoic membrane (CAM) model. Moreover, the combination of Talazoparib and the CDK4/6 inhibitor Palbociclib synergistically reduced tumor growth in Retinoblastoma protein (RB)-positive BLCA in vitro and in a CAM model, an effect that relies on Palbociclib-induced cell cycle arrest in G0/G1-phase complemented by a G2 arrest induced by Talazoparib. Interestingly, Talazoparib-induced apoptosis was reduced by Palbociclib. The combination of Palbociclib and Talazoparib effectively enhances BLCA therapy, and RB is a molecular biomarker of response to this treatment regimen.
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页数:15
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