Li Xu, Guo Yingwei, Qi Zecheng, Zheng Yi
Department of Cardiothoracic Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou City.
Department of Urology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, China.
Anticancer Drugs. 2025 Apr 1;36(4):319-327. doi: 10.1097/CAD.0000000000001682. Epub 2025 Jan 14.
Chemotherapy resistance has long stood in the way of therapeutic advancement for lung cancer patients, the malignant tumor with the highest incidence and fatality rate in the world. Patients with lung adenocarcinoma (LUAD) now have a dismal prognosis due to the development of cisplatin (DDP) resistance, forcing them to use more costly second-line therapies. Therefore, overcoming resistance and enhancing patient outcomes can be achieved by comprehending the regulatory mechanisms of DDP resistance in LUAD. WD repeat domain 62 (WDR62) expression in LUAD tissues and in DDP-resistant or sensitive LUAD patients was analyzed bioinformatically, and a K-M plot was utilized to assess survival status. Real-time quantitative PCR was employed for WDR62 expression detection, cell-counting kit-8 assay for half maximal inhibitory concentration determination, flow cytometry for cell apoptosis detection, immunofluorescence for γ-H2AX expression analysis, and western blot for nonhomologous end joining repair and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway-related protein expression analysis. Poor prognosis was linked to WDR62, which was overexpressed in LUAD tissues and cells. Compared to sensitive cells, DDP-resistant cells had increased WDR62 expression. WDR62 knockdown may enhance DDP-induced cell apoptosis while reducing cell proliferation and DNA damage repair. Functional investigations verified that overexpressed WDR62's encouraging impact on DNA damage repair in A549/DDP cells could be reversed by MAPK inhibitors, increasing the cells' susceptibility to DDP. LUAD cells became less sensitive to DDP when WDR62 activated the MAPK/ERK pathway, which promoted DNA damage repair, indicating that DDP resistance might be reversed by treating LUAD with inhibitors of the MAPK pathway.
化疗耐药长期以来一直阻碍着肺癌患者的治疗进展，肺癌是全球发病率和死亡率最高的恶性肿瘤。由于顺铂（DDP）耐药的出现，肺腺癌（LUAD）患者目前预后不佳，迫使他们使用成本更高的二线治疗方法。因此，通过了解LUAD中DDP耐药的调控机制，可以克服耐药性并改善患者预后。通过生物信息学分析LUAD组织以及DDP耐药或敏感的LUAD患者中WD重复结构域62（WDR62）的表达，并利用K-M图评估生存状况。采用实时定量PCR检测WDR62表达，细胞计数试剂盒-8法测定半数最大抑制浓度，流式细胞术检测细胞凋亡，免疫荧光分析γ-H2AX表达，蛋白质免疫印迹法分析非同源末端连接修复以及丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）通路相关蛋白的表达。预后不良与WDR62有关，WDR62在LUAD组织和细胞中过表达。与敏感细胞相比，DDP耐药细胞中WDR62表达增加。敲低WDR62可能会增强DDP诱导的细胞凋亡，同时减少细胞增殖和DNA损伤修复。功能研究证实，MAPK抑制剂可逆转过表达的WDR62对A549/DDP细胞DNA损伤修复的促进作用，增加细胞对DDP的敏感性。当WDR62激活促进DNA损伤修复的MAPK/ERK通路时，LUAD细胞对DDP的敏感性降低，这表明用MAPK通路抑制剂治疗LUAD可能会逆转DDP耐药。
