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

Chandra Bhushan Prasad, Adrian Oo, Yujie Liu, Zhaojun Qiu, Yaogang Zhong, Na Li, Deepika Singh, Xiwen Xin, Young-Jae Cho, Zaibo Li, Xiaoli Zhang, Chunhong Yan, Qingfei Zheng, Qi-En Wang, Deliang Guo, Baek Kim and Junran Zhang ()
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Chandra Bhushan Prasad: The Ohio State University
Adrian Oo: Emory University
Yujie Liu: The Ohio State University
Zhaojun Qiu: The Ohio State University
Yaogang Zhong: The Ohio State University
Na Li: The Ohio State University
Deepika Singh: The Ohio State University
Xiwen Xin: The Ohio State University
Young-Jae Cho: Emory University
Zaibo Li: College of Medicine
Xiaoli Zhang: The Ohio State University
Chunhong Yan: Augusta University
Qingfei Zheng: The Ohio State University
Qi-En Wang: The Ohio State University
Deliang Guo: The Ohio State University
Baek Kim: Emory University
Junran Zhang: The Ohio State University

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-48076-9

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