Qin Siyuan, Zhang Zhe, Huang Zhao, Luo Yinheng, Weng Ningna, Li Bowen, Tang Yongquan, Zhou Li, Jiang Jingwen, Lu Yi, Shao Jichun, Xie Na, Nice Edouard C, Chen Zhe-Sheng, Zhang Jian, Huang Canhua
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
Department of Abdominal Oncology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, China.
Drug Resist Updat. 2023 Jan;66:100906. doi: 10.1016/j.drup.2022.100906. Epub 2022 Nov 30.
It was well known that P-glycoprotein (P-gp/ABCB1) is a master regulator of multidrug resistance (MDR) in cancers. However, the clinical benefit from blocking this pathway remains inconclusive, which motivates a paradigm shift towards alternative strategies for enhancing drug influx. Using a patient-derived organoid (PDO)-based drug screening platform, we report that the combined use of chemotherapy and CCT251545 (CCT) displays robust synergistic effect against PDOs and reduces proliferation of MDR cancer cells in vitro, and results in regression of xenograft tumors, reductions in metastatic dissemination and recurrence rate in vivo. The synergistic activity mediated by CCT can be mainly attributed to the intense uptake of chemotherapeutic agents into the cells, accompanied by alterations in cell phenotypes defined as a mesenchymal epithelial transformation (MET). Mechanistically, analysis of the transcriptome coupled with validation in cellular and animal models demonstrate that the chemosensitizing effect of CCT is profoundly affected by Rac1-dependent macropinocytosis. Furthermore, CCT binds to NAMPT directly, resulting in elevated NAD levels within MDR cancer cells. This effect promotes the assembly of adherents junction (AJ) components with cytoskeleton, which is required for continuous induction of macropinocytosis and consequent drug internalization. Overall, our results illustrate the potential use of CCT as a combination partner for the commonly used chemotherapeutic drugs in the management of MDR cancers.
众所周知，P-糖蛋白（P-gp/ABCB1）是癌症多药耐药性（MDR）的主要调节因子。然而，阻断该途径的临床益处仍不明确，这促使人们转向采用替代策略来增强药物内流。利用基于患者来源类器官（PDO）的药物筛选平台，我们报告称，化疗与CCT251545（CCT）联合使用对PDO显示出强大的协同效应，并在体外降低MDR癌细胞的增殖，且在体内导致异种移植肿瘤消退、转移扩散减少和复发率降低。CCT介导的协同活性主要归因于化疗药物大量摄入细胞，同时伴随着细胞表型的改变，即间充质上皮转化（MET）。从机制上讲，转录组分析以及在细胞和动物模型中的验证表明，CCT的化学增敏作用受到Rac1依赖性巨胞饮作用的深刻影响。此外，CCT直接与NAMPT结合，导致MDR癌细胞内NAD水平升高。这种效应促进了黏附连接（AJ）成分与细胞骨架组装，这是持续诱导巨胞饮作用及随后药物内化所必需的。总体而言，我们的结果说明了CCT作为常用化疗药物联合用药伙伴在MDR癌症治疗中的潜在用途。
