Inhibition of Thioredoxin/Thioredoxin Reductase Induces Synthetic Lethality in Lung Cancers with Compromised Glutathione Homeostasis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-01, Vol.79 (1), p.125-132
• Main Authors: Yan, Xiang, Zhang, Xiaoshan, Wang, Li, Zhang, Ran, Pu, Xingxiang, Wu, Shuhong, Li, Lei, Tong, Pan, Wang, Jing, Meng, Qing H, Jensen, Vanessa B, Girard, Luc, Minna, John D, Roth, Jack A, Swisher, Stephen G, Heymach, John V, Fang, Bingliang
• Format: Article
• Language: English
• Subjects: Animals; Antirheumatic Agents - pharmacology; 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 Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Glutamate-Cysteine Ligase - genetics; Glutamate-Cysteine Ligase - metabolism; Glutathione - metabolism; Glutathione Reductase - genetics; Glutathione Reductase - metabolism; Homeostasis; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Mice, Inbred NOD; Mice, SCID; Synthetic Lethal Mutations; Thioredoxin-Disulfide Reductase - genetics; Thioredoxin-Disulfide Reductase - metabolism; Thioredoxins - genetics; Thioredoxins - metabolism; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-18-1938

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 gene is located on chromosome 8p12, a region frequently lost in human cancers. deletion was detected in about 6% of lung adenocarcinomas in The Cancer Genome Atlas database. To test whether loss of sensitizes cancer cells to TXNRD inhibition, we knocked out or knocked down the gene in human lung cancer cells and evaluated their response to the TXNRD inhibitor auranofin. 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 , glutamate-cysteine ligase catalytic subunit ( ), and NAD(P)H quinone dehydrogenase 1 ( ) genes. In NSCLC patient-derived xenografts with reduced expression of and/or , 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 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 gene expression, may be targeted by thioredoxin/thioredoxin reductase inhibitors.