IMPDH inhibition induces DNA replication stress and ATR sensitivity in Merkel cell carcinoma

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-05-02 DOI:10.1016/j.isci.2025.112567

Julia L. Schnabel , Thomas C. Frost , Adam C. Wang , Varsha Ananthapadmanabhan , Satvik Gurram , Kara M. Soroko , Prafulla C. Gokhale , James A. DeCaprio

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Abstract

The rate-limiting isozyme of de novo guanosine biosynthesis, IMPDH2, was identified as an essential gene in Merkel cell carcinoma (MCC) but the consequences of its functional disruption were unclear. Inhibition of IMPDH2 led to reduced MCC cell viability, independent of functional p53 or Merkel cell polyomavirus status, but dependent on depletion of guanylate nucleotides. In contrast to other cancer models, inhibition of IMPDH2 in MCC led to rapid ablation of nascent DNA synthesis and the onset of replication stress without a significant effect on total or ribosomal RNA biosynthesis. Combining IMPDH inhibitors with ataxia telangiectasia mutated and Rad3-related (ATR) inhibitors significantly increased levels of replication stress in vitro and reduced tumor growth in vivo. These findings support replication stress as the dominant consequence of IMPDH2 inhibition in MCC and, when combined with ATR inhibition, indicate a potential therapeutic strategy.

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在默克尔细胞癌中抑制IMPDH诱导DNA复制应激和ATR敏感性

新的鸟苷生物合成的限速同工酶IMPDH2被确定为默克尔细胞癌（MCC）的一个必需基因，但其功能破坏的后果尚不清楚。抑制IMPDH2导致MCC细胞活力降低，独立于功能p53或默克尔细胞多瘤病毒状态，但依赖于鸟苷酸核苷酸的消耗。与其他癌症模型相比，MCC中抑制IMPDH2导致新生DNA合成的快速消融和复制应激的发生，而对总RNA或核糖体RNA的生物合成没有显著影响。将IMPDH抑制剂与共济失调毛细血管扩张突变和rad3相关（ATR）抑制剂联合使用，在体外显著增加复制应激水平，在体内显著降低肿瘤生长。这些发现支持复制应激是MCC中IMPDH2抑制的主要后果，并且当与ATR抑制联合使用时，表明了一种潜在的治疗策略。

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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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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