BH3-mimetics or DNA-damaging agents in combination with RG7388 overcome p53 mutation-induced resistance to MDM2 inhibition.

IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Apoptosis Pub Date : 2024-12-01 Epub Date: 2024-09-02 DOI:10.1007/s10495-024-02014-8
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
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引用次数: 0

Abstract

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.

Abstract Image

BH3模拟物或DNA损伤剂与RG7388联合使用,可克服p53突变诱导的对MDM2抑制的耐药性。
耐药性的产生会降低癌症疗法的疗效。肿瘤细胞会对 MDM2 抑制剂产生耐药性,目前这些抑制剂正在接受临床评估。与野生型细胞相比,我们培育出了对 RG7388 产生耐药性的神经母细胞瘤细胞,它们在体外和体内都变得更加增殖和代谢活跃,对 DNA 损伤药物的敏感性也更低。这种抗药性与 p53 蛋白的突变(His193Arg)有关。这种突变通过破坏 p53-DNA 四聚体复合物的稳定性来削弱其转录活性,在许多癌症类型中都能观察到这种突变。最后,我们发现顺铂和各种BH3模拟物可以增强RG7388介导的、对RG7388耐药的神经母细胞瘤细胞的凋亡,从而部分克服对MDM2抑制的耐药性。
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来源期刊
Apoptosis
Apoptosis 生物-生化与分子生物学
CiteScore
9.10
自引率
4.20%
发文量
85
审稿时长
1 months
期刊介绍: Apoptosis, a monthly international peer-reviewed journal, focuses on the rapid publication of innovative investigations into programmed cell death. The journal aims to stimulate research on the mechanisms and role of apoptosis in various human diseases, such as cancer, autoimmune disease, viral infection, AIDS, cardiovascular disease, neurodegenerative disorders, osteoporosis, and aging. The Editor-In-Chief acknowledges the importance of advancing clinical therapies for apoptosis-related diseases. Apoptosis considers Original Articles, Reviews, Short Communications, Letters to the Editor, and Book Reviews for publication.
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