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BH3 模拟物或 DNA 损伤剂与 RG7388 联合克服了 p53 突变诱导的对 MDM2 抑制的耐药性。

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

机构信息

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.

Faculty of Medicine, MV Lomonosov Moscow State University, Moscow, 119991, Russia.

出版信息

Apoptosis. 2024 Dec;29(11-12):2197-2213. doi: 10.1007/s10495-024-02014-8. Epub 2024 Sep 2.

DOI:10.1007/s10495-024-02014-8
PMID:39222276
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11550243/
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.

摘要

耐药性的发展降低了癌症治疗的疗效。肿瘤细胞可以获得对 MDM2 抑制剂的耐药性，目前正在进行临床评估。我们生成了对 RG7388 具有耐药性的神经母细胞瘤细胞，与野生型细胞相比，这些细胞在体外和体内具有更高的增殖和代谢活性，对 DNA 损伤剂的敏感性降低。耐药性与 p53 蛋白（His193Arg）的突变有关。这种突变通过使四聚体 p53-DNA 复合物不稳定来减弱其转录活性，并且在许多癌症类型中都有观察到。最后，我们发现顺铂和各种 BH3 模拟物可以增强 RG7388 介导的 RG7388 耐药性神经母细胞瘤细胞中的细胞凋亡，从而部分克服对 MDM2 抑制的耐药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/4f8da066d1e6/10495_2024_2014_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/46c1c70c9b51/10495_2024_2014_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/4d3bac6a1929/10495_2024_2014_Fig5_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/51d2c5ce1088/10495_2024_2014_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/c26aadc29248/10495_2024_2014_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/decc3d7a02f0/10495_2024_2014_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/4f8da066d1e6/10495_2024_2014_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/46c1c70c9b51/10495_2024_2014_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/b5b58f904dab/10495_2024_2014_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/fc3ccb823af2/10495_2024_2014_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/c8a16c60bd15/10495_2024_2014_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/4d3bac6a1929/10495_2024_2014_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/8a5cf6aa5897/10495_2024_2014_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/51d2c5ce1088/10495_2024_2014_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/c26aadc29248/10495_2024_2014_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/decc3d7a02f0/10495_2024_2014_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8aa6/11550243/4f8da066d1e6/10495_2024_2014_Fig10_HTML.jpg

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