Therapy enhancing chromosome instability may be advantageous for IDH1 R132H/WT gliomas.

IF 3.4 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
NAR cancer Pub Date : 2025-02-13 eCollection Date: 2025-03-01 DOI:10.1093/narcan/zcaf003
Nikolay V Goncharov, Ivan N Baklanov, Valeriia S Gulaia, Anastasiia P Shuliak, Daria V Lanskikh, Valeriia M Zhmenia, Mikhail E Shmelev, Nikita A Shved, Jing Wu, Mikhail Liskovykh, Vladimir Larionov, Natalay Kouprina, Vadim V Kumeiko
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引用次数: 0

Abstract

Recently revised brain tumor classification suggested a glioma treatment strategy that takes into consideration molecular variants in IDH1 and TP53 marker genes. While pathogenic variants of IDH1 and TP53 can be accompanied by chromosomal instability (CIN), the impact of IDH1 and TP53 mutations on genome stability remains unstudied. Elevated CIN might provide therapeutic targets, based on synergistic effects of chemotherapy with CIN-inducing drugs. Using an assay based on human artificial chromosomes, we investigated the impact of common glioma missense mutations in IDH1 and TP53 on chromosome transmission and demonstrated that IDH1R132H and TP53R248Q variants elevate CIN. We next found enhanced CIN levels and the sensitivity of IDH1 R132H/WT and TP53 R248Q/R248Q genotypes, introduced into U87 MG glioma cells by CRISPR/Cas9, to different drugs, including conventional temozolomide. It was found that U87 MG cells carrying IDH1 R132H/WT exhibit dramatic sensitivity to paclitaxel, which was independently confirmed on cell cultures derived from patients with naturally occurring IDH1 R132H/WT. Overall, our results suggest that the development of CIN-enhancing therapy for glioma tumors with the IDH1 R132H/WT genotype could be advantageous for adjuvant treatment.

增强染色体不稳定性的治疗可能对IDH1 R132H/WT胶质瘤有利。
最近修订的脑肿瘤分类提出了一种考虑IDH1和TP53标记基因分子变异的胶质瘤治疗策略。虽然IDH1和TP53的致病变异可伴有染色体不稳定性(CIN),但IDH1和TP53突变对基因组稳定性的影响尚未研究。基于化疗与CIN诱导药物的协同作用,升高的CIN可能提供治疗靶点。利用基于人类人工染色体的实验,我们研究了常见的胶质瘤错义突变IDH1和TP53对染色体传递的影响,并证明IDH1R132H和TP53R248Q变体提高了CIN。接下来,我们发现通过CRISPR/Cas9导入U87 MG胶质瘤细胞的IDH1 R132H/WT和TP53 R248Q/R248Q基因型对不同药物(包括常规替莫唑胺)的CIN水平和敏感性增强。研究发现,携带IDH1 R132H/WT的U87 MG细胞对紫杉醇表现出显著的敏感性,这在自然发生的IDH1 R132H/WT患者的细胞培养中得到了独立证实。总之,我们的研究结果表明,开发针对IDH1 R132H/WT基因型胶质瘤的cin增强疗法可能有利于辅助治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
6.90
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审稿时长
13 weeks
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