Division of Hematology Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 83301, Taiwan.
Genomic & Proteomic Core Laboratory, Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
Cells. 2023 May 25;12(11):1471. doi: 10.3390/cells12111471.
Urothelial carcinoma (UC) is characterized by a high incidence of mutation, and overcoming resistance to cisplatin-based chemotherapy in UC is a major concern. Wee1 is a G2/M phase regulator that controls the DNA damage response to chemotherapy in -mutant cancers. The combination of Wee1 blockade with cisplatin has shown synergistic efficacy in several types of cancers, but little is known regarding UC. The antitumor efficacy of the Wee1 inhibitor (AZD-1775) alone or in combination with cisplatin was evaluated in UC cell lines and a xenograft mouse model. AZD-1775 enhanced the anticancer activity of cisplatin by increasing cellular apoptosis. AZD-1775 inhibited the G2/M checkpoint, improving the sensitivity of mutant UC cells to cisplatin by enhancing the DNA damage process. We confirmed that AZD-1775 combined with cisplatin reduced tumor volume and proliferation activity and increased the markers of cell apoptosis and DNA damage in the mouse xenograft model. In summary, the Wee1 inhibitor AZD-1775 combined with cisplatin elicited a promising anticancer efficacy in UC, and constitutes an innovative and promising therapeutic strategy.
尿路上皮癌（UC）的特点是 突变发生率高，克服 UC 对顺铂为基础的化疗的耐药性是一个主要关注点。Wee1 是 G2/M 期调控因子，可控制 -突变癌症对化疗的 DNA 损伤反应。Wee1 抑制剂与顺铂联合使用已在多种类型的癌症中显示出协同疗效，但关于 UC 的研究甚少。在 UC 细胞系和异种移植小鼠模型中评估了 Wee1 抑制剂（AZD-1775）单独或联合顺铂的抗肿瘤疗效。AZD-1775 通过增加细胞凋亡增强了顺铂的抗癌活性。AZD-1775 抑制 G2/M 检查点，通过增强 DNA 损伤过程，提高了突变型 UC 细胞对顺铂的敏感性。我们证实，AZD-1775 联合顺铂可降低肿瘤体积和增殖活性，并增加小鼠异种移植模型中细胞凋亡和 DNA 损伤的标志物。总之，Wee1 抑制剂 AZD-1775 联合顺铂在 UC 中产生了有前途的抗肿瘤疗效，构成了一种创新且有前途的治疗策略。
