BH3 模拟物或 DNA 损伤剂与 RG7388 联合克服了 p53 突变诱导的 MDM2 抑制耐药性。
BH3-mimetics or DNA-damaging agents in combination with RG7388 overcome p53 mutation-induced resistance to MDM2 inhibition.
发表日期：2024 Sep 02
作者：
N V Pervushin, D K Nilov, S V Pushkarev, V O Shipunova, A S Badlaeva, M A Yapryntseva, D V Kopytova, B Zhivotovsky, G S Kopeina
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
耐药性的发展降低了癌症治疗的功效。肿瘤细胞可以获得对MDM2抑制剂的耐药性，目前正在临床评估中。我们生成了 RG7388 抗性神经母细胞瘤细胞，与野生型细胞相比，其增殖能力和代谢活性更高，并且在体外和体内对 DNA 损伤剂的敏感性较低。这种耐药性与 p53 蛋白 (His193Arg) 的突变有关。这种突变通过四聚体 p53-DNA 复合物的不稳定来减弱其转录活性，并在许多癌症类型中观察到。最后，我们发现顺铂和各种 BH3 模拟物可以增强 RG7388 耐药神经母细胞瘤细胞中 RG7388 介导的细胞凋亡，从而部分克服对 MDM2 抑制的耐药性。© 2024。作者。
The development of drug resistance reduces the efficacy of cancer therapy. Tumor cells can acquire resistance to MDM2 inhibitors, which are currently under clinical evaluation. We generated RG7388-resistant neuroblastoma cells, which became more proliferative and metabolically active and were less sensitive to DNA-damaging agents in vitro and in vivo, compared with wild-type cells. The resistance was associated with a mutation of the p53 protein (His193Arg). This mutation abated its transcriptional activity via destabilization of the tetrameric p53-DNA complex and was observed in many cancer types. Finally, we found that Cisplatin and various BH3-mimetics could enhance RG7388-mediated apoptosis in RG7388-resistant neuroblastoma cells, thereby partially overcoming resistance to MDM2 inhibition.© 2024. The Author(s).