Zanini Elisa, Forster-Gross Nicole, Bachmann Felix, Brüngger Adrian, McSheehy Paul, Litherland Karine, Burger Karin, Groner Anna C, Roceri Mila, Bury Luc, Stieger Martin, Willemsen-Seegers Nicole, de Man Jos, Vu-Pham Diep, van Riel Helma W E, Zaman Guido J R, Buijsman Rogier C, Kellenberger Laurenz, Lane Heidi A
Basilea Pharmaceutica International Ltd, Allschwil, Switzerland.
Oncolines B.V., Oss, Netherlands.
Front Oncol. 2024 Aug 9;14:1447807. doi: 10.3389/fonc.2024.1447807. eCollection 2024.
Threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) are common essential kinases that collaborate in activating the spindle assembly checkpoint (SAC) at the kinetochore, ensuring appropriate chromosome alignment and segregation prior to mitotic exit. Targeting of either TTK or PLK1 has been clinically evaluated in cancer patients; however, dual inhibitors have not yet been pursued. Here we present the and characterization of a first in class, dual TTK/PLK1 inhibitor (BAL0891).
Mechanism of action studies utilized biochemical kinase and proteomics-based target-engagement assays. Cellular end-point assays included immunoblot- and flow cytometry-based cell cycle analyses and SAC integrity evaluation using immunoprecipitation and immunofluorescence approaches. Anticancer activity was assessed using cell growth assays and efficacy was evaluated, alone and in combination with paclitaxel and carboplatin, using mouse models of triple negative breast cancer (TNBC).
BAL0891 elicits a prolonged effect on TTK, with a transient activity on PLK1. This unique profile potentiates SAC disruption, forcing tumor cells to aberrantly exit mitosis with faster kinetics than observed with a TTK-specific inhibitor. Broad anti-proliferative activity was demonstrated across solid tumor cell lines . Moreover, intermittent intravenous single-agent BAL0891 treatment of the MDA-MB-231 mouse model of TNBC induced profound tumor regressions associated with prolonged TTK and transient PLK1 in-tumor target occupancy. Furthermore, differential tumor responses across a panel of thirteen TNBC patient-derived xenograft models indicated profound anticancer activity in a subset (~40%). Using a flexible dosing approach, pathologically confirmed cures were observed in combination with paclitaxel, whereas synergy with carboplatin was schedule dependent.
Dual TTK/PLK1 inhibition represents a novel approach for the treatment of human cancer, including TNBC patients, with a potential for potent anticancer activity and a favorable therapeutic index. Moreover, combination approaches may provide an avenue to expand responsive patient populations.
苏氨酸酪氨酸激酶（TTK）和波罗样激酶1（PLK1）是常见的必需激酶，它们协同作用于动粒激活纺锤体组装检查点（SAC），确保在有丝分裂退出之前染色体正确排列和分离。针对TTK或PLK1的靶向治疗已在癌症患者中进行了临床评估；然而，双抑制剂尚未得到研究。在此，我们展示了首个双TTK/PLK1抑制剂（BAL0891）的发现及特性。
作用机制研究采用了基于生化激酶和蛋白质组学的靶点结合分析。细胞终点分析包括基于免疫印迹和流式细胞术的细胞周期分析，以及使用免疫沉淀和免疫荧光方法评估SAC完整性。使用细胞生长分析评估抗癌活性，并使用三阴性乳腺癌（TNBC）小鼠模型单独或与紫杉醇和卡铂联合评估疗效。
BAL0891对TTK有持久作用，对PLK1有短暂活性。这种独特的特性增强了SAC破坏，迫使肿瘤细胞以比TTK特异性抑制剂更快的动力学异常退出有丝分裂。在多种实体瘤细胞系中均显示出广泛的抗增殖活性。此外，对TNBC的MDA-MB-231小鼠模型进行间歇性静脉内单药BAL0891治疗，可诱导肿瘤显著消退，这与肿瘤内TTK持久和PLK1短暂的靶点占有率相关。此外，在一组13个TNBC患者来源的异种移植模型中观察到不同的肿瘤反应，表明在一部分患者（约40%）中具有显著的抗癌活性。采用灵活的给药方法，与紫杉醇联合使用时观察到经病理证实的治愈，而与卡铂的协同作用则依赖于给药方案。
双TTK/PLK1抑制代表了一种治疗人类癌症（包括TNBC患者）的新方法，具有强大的抗癌活性和良好的治疗指数潜力。此外，联合治疗方法可能为扩大反应性患者群体提供途径。
