The thioredoxin system determines CHK1 inhibitor sensitivity via redox-mediated regulation of ribonucleotide reductase activity

Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i’s) in combination with chemotherapy have shown promising results in preclinical studies but have displayed minimal efficacy with substantial toxicity in clinical trials. To explore combinat...

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Veröffentlicht in:	Nature communications Jg. 15; H. 1; S. 4667 - 23
Hauptverfasser:	Prasad, Chandra Bhushan, Oo, Adrian, Liu, Yujie, Qiu, Zhaojun, Zhong, Yaogang, Li, Na, Singh, Deepika, Xin, Xiwen, Cho, Young-Jae, Li, Zaibo, Zhang, Xiaoli, Yan, Chunhong, Zheng, Qingfei, Wang, Qi-En, Guo, Deliang, Kim, Baek, Zhang, Junran
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 31.05.2024 Nature Publishing Group Nature Portfolio
Schlagworte:	13 13/106 13/2 42 42/70 49 49/47 631/67/1612 631/67/1612/1350 64 64/60 692/4028/67/1059/2326 Animals Auranofin - pharmacology Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Cell Line, Tumor Cell survival Checkpoint Kinase 1 - antagonists & inhibitors Checkpoint Kinase 1 - metabolism Chemotherapy CHK1 protein Clinical trials Combinatorial analysis Drug Synergism Effectiveness Humanities and Social Sciences Humans Inhibitors Kinases Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - metabolism Lung Neoplasms - pathology Mammals multidisciplinary Non-small cell lung carcinoma Oxidation-Reduction - drug effects Protein Kinase Inhibitors - pharmacology Reductase Reductases Rheumatoid arthritis Ribonucleoside Diphosphate Reductase - genetics Ribonucleoside Diphosphate Reductase - metabolism Ribonucleotide reductase Ribonucleotide Reductases - antagonists & inhibitors Ribonucleotide Reductases - metabolism Science Science (multidisciplinary) Sensitivity Small cell lung carcinoma Synergistic effect Thioredoxin Thioredoxins - metabolism Toxicity
ISSN:	2041-1723, 2041-1723
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Zusammenfassung:	Checkpoint kinase 1 (CHK1) is critical for cell survival under replication stress (RS). CHK1 inhibitors (CHK1i’s) in combination with chemotherapy have shown promising results in preclinical studies but have displayed minimal efficacy with substantial toxicity in clinical trials. To explore combinatorial strategies that can overcome these limitations, we perform an unbiased high-throughput screen in a non-small cell lung cancer (NSCLC) cell line and identify thioredoxin1 (Trx1), a major component of the mammalian antioxidant-system, as a determinant of CHK1i sensitivity. We establish a role for redox recycling of RRM1, the larger subunit of ribonucleotide reductase (RNR), and a depletion of the deoxynucleotide pool in this Trx1-mediated CHK1i sensitivity. Further, the TrxR inhibitor auranofin, an approved anti-rheumatoid arthritis drug, shows a synergistic interaction with CHK1i via interruption of the deoxynucleotide pool. Together, we show a pharmacological combination to treat NSCLC that relies on a redox regulatory link between the Trx system and mammalian RNR activity. The clinical application of inhibitors targeting checkpoint kinase 1 (CHK1) is challenged by limited efficacy. Here, the authors identify that thioredoxin (Trx) system inhibition mediates sensitivity to CHK1 inhibitor via regulating the activity of ribonucleotide reductase, demonstrating the synergistic effect of CHK1 inhibitor and inhibitors targeting Trx system in lung cancer models.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-48076-9