Inhibition of thioredoxin/thioredoxin reductase induces synthetic lethality in lung cancers with compromised glutathione homeostasis

Xiang Yan, Xiaoshan Zhang, Li Wang, Ran Zhang, Xingxiang Pu, Shuhong Wu, Lei Li, Pan Tong, Jing Wang, Qing H. Meng, Vanessa B. Jensen, Luc Girard, John D Minna, Jack A. Roth, Stephen G. Swisher, John V. Heymach, Bingliang Fang

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Glutathione (GSH)/GSH reductase (GSR) and thioredoxin/ thioredoxin reductase (TXNRD) are two major compensating thiol-dependent antioxidant pathways that maintain protein dithiol/disulfide balance. We hypothesized that functional deficiency in one of these systems would render cells dependent on compensation by the other system for survival, providing a mechanism-based synthetic lethality approach for treatment of cancers. The human GSR gene is located on chromosome 8p12, a region frequently lost in human cancers. GSR deletion was detected in about 6% of lung adenocarcinomas in The Cancer Genome Atlas database. To test whether loss of GSR sensitizes cancer cells to TXNRD inhibition, we knocked out or knocked down the GSR gene in human lung cancer cells and evaluated their response to the TXNRD inhibitor auranofin. GSR deficiency sensitized lung cancer cells to this agent. Analysis of a panel of 129 non–small cell lung cancer (NSCLC) cell lines revealed that auranofin sensitivity correlated with the expression levels of the GSR, glutamate-cysteine ligase catalytic subunit (GCLC), and NAD(P)H qui-none dehydrogenase 1 (NQO1) genes. In NSCLC patient-derived xenografts with reduced expression of GSR and/or GCLC, growth was significantly suppressed by treatment with auranofin. Together, these results provide a proof of concept that cancers with compromised expression of enzymes required for GSH homeostasis or with chromosome 8p deletions that include the GSR gene may be targeted by a synthetic lethality strategy with inhibitors of TXNRD. Significance: These findings demonstrate that lung cancers with compromised expression of enzymes required for glutathione homeostasis, including reduced GSR gene expression, may be targeted by thioredoxin/thioredoxin reductase inhibitors.

Original languageEnglish (US)
Pages (from-to)125-132
Number of pages8
JournalCancer Research
Volume79
Issue number1
DOIs
StatePublished - Jan 1 2019

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Yan, X., Zhang, X., Wang, L., Zhang, R., Pu, X., Wu, S., Li, L., Tong, P., Wang, J., Meng, Q. H., Jensen, V. B., Girard, L., Minna, J. D., Roth, J. A., Swisher, S. G., Heymach, J. V., & Fang, B. (2019). Inhibition of thioredoxin/thioredoxin reductase induces synthetic lethality in lung cancers with compromised glutathione homeostasis. Cancer Research, 79(1), 125-132. https://doi.org/10.1158/0008-5472.CAN-18-1938