Klein Florian G, Granier Charlène, Zhao Yuling, Pan Qi, Tong Zhichao, Gschwend Jürgen E, Holm Per Sonne, Nawroth Roman
Department of Urology, Klinikum Rechts der Isar, Technical University of Munich, D-81675 Munich, Germany.
Department of Oral and Maxillofacial Surgery, Medical University Innsbruck, A-6020 Innsbruck, Austria.
J Pers Med. 2021 Apr 24;11(5):340. doi: 10.3390/jpm11050340.
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.
细胞周期蛋白依赖性激酶4/6（CDK4/6）抑制剂的使用是一种有效的癌症治疗策略。由于调节细胞周期进程的分子网络复杂，癌细胞常常获得针对这些抑制剂的耐药机制。此前，我们团队鉴定出了赋予膀胱癌（BLCA）对CDK4/6抑制耐药的分子因子，其中还包括DNA修复途径中的成分。在本研究中，我们验证了CDK4/6抑制剂哌柏西利与聚（ADP - 核糖）聚合酶（PARP）抑制剂联合治疗方法是否能改善BLCA的治疗反应。首先，对PARP抑制剂他拉唑帕利和奥拉帕利的比较显示，他拉唑帕利在体外具有更高的疗效，并且在鸡胚绒毛尿囊膜（CAM）模型的异种移植中表现出高抗肿瘤活性。此外，他拉唑帕利与CDK4/6抑制剂哌柏西利联合使用在体外和CAM模型中协同降低了视网膜母细胞瘤蛋白（RB）阳性BLCA的肿瘤生长，这种效应依赖于哌柏西利诱导的G0/G1期细胞周期停滞，并由他拉唑帕利诱导的G2期停滞加以补充。有趣的是，哌柏西利降低了他拉唑帕利诱导的细胞凋亡。哌柏西利和他拉唑帕利联合使用可有效增强BLCA治疗效果，并且RB是对该治疗方案反应的分子生物标志物。
