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

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 <i>GSR</i> gene is located on chromosome 8p12, a region frequently lost in human cancers. <i>GSR</i> deletion was detected in about 6% of lung adenocarcinomas in The Cancer Genome Atlas database. To test whether loss of <i>GSR</i> sensitizes cancer cells to TXNRD inhibition, we knocked out or knocked down the <i>GSR</i> gene in human lung cancer cells and evaluated their response to the TXNRD inhibitor auranofin. <i>GSR</i> 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 <i>GSR</i>, glutamate-cysteine ligase catalytic subunit (<i>GCLC</i>), and NAD(P)H quinone dehydrogenase 1 (<i>NQO1</i>) genes. In NSCLC patient-derived xenografts with reduced expression of <i>GSR</i> and/or <i>GCLC</i>, 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 <i>GSR</i> 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 <i>GSR</i> gene expression, may be targeted by thioredoxin/thioredoxin reductase inhibitors.