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肿瘤酸中毒诱导的DNA损伤反应和四倍体增强了对ATM和ATR抑制剂的敏感性。

Tumor acidosis-induced DNA damage response and tetraploidy enhance sensitivity to ATM and ATR inhibitors.

作者信息

Aubert Léo, Bastien Estelle, Renoult Ophélie, Guilbaud Céline, Özkan Kübra, Brusa Davide, Bouzin Caroline, Richiardone Elena, Richard Corentin, Boidot Romain, Léonard Daniel, Corbet Cyril, Feron Olivier

机构信息

Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, B-1200, Brussels, Belgium.

CytoFlux-Flow Cytometry and Cell Sorting Platform, Institut de Recherche Expérimentale et Clinique (IREC), UCLouvain, B-1200, Brussels, Belgium.

出版信息

EMBO Rep. 2024 Mar;25(3):1469-1489. doi: 10.1038/s44319-024-00089-7. Epub 2024 Feb 16.

DOI:10.1038/s44319-024-00089-7
PMID:38366255
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10933359/
Abstract

Tumor acidosis is associated with increased invasiveness and drug resistance. Here, we take an unbiased approach to identify vulnerabilities of acid-exposed cancer cells by combining pH-dependent flow cytometry cell sorting from 3D colorectal tumor spheroids and transcriptomic profiling. Besides metabolic rewiring, we identify an increase in tetraploid cell frequency and DNA damage response as consistent hallmarks of acid-exposed cancer cells, supported by the activation of ATM and ATR signaling pathways. We find that regardless of the cell replication error status, both ATM and ATR inhibitors exert preferential growth inhibitory effects on acid-exposed cancer cells. The efficacy of a combination of these drugs with 5-FU is further documented in 3D spheroids as well as in patient-derived colorectal tumor organoids. These data position tumor acidosis as a revelator of the therapeutic potential of DNA repair blockers and as an attractive clinical biomarker to predict the response to a combination with chemotherapy.

摘要

肿瘤酸中毒与侵袭性增加和耐药性相关。在此，我们采用一种无偏倚的方法，通过结合从三维结直肠肿瘤球体中进行的pH依赖性流式细胞术细胞分选和转录组分析，来识别暴露于酸性环境的癌细胞的脆弱性。除了代谢重编程外，我们还发现四倍体细胞频率增加和DNA损伤反应是暴露于酸性环境的癌细胞的一致特征，这得到了ATM和ATR信号通路激活的支持。我们发现，无论细胞复制错误状态如何，ATM和ATR抑制剂对暴露于酸性环境的癌细胞都具有优先的生长抑制作用。这些药物与5-氟尿嘧啶联合使用的疗效在三维球体以及患者来源的结直肠肿瘤类器官中得到了进一步证实。这些数据表明肿瘤酸中毒是DNA修复阻滞剂治疗潜力的揭示者，也是预测联合化疗反应的有吸引力的临床生物标志物。

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