KEAP1-Dependent Synthetic Lethality Induced by AKT and TXNRD1 Inhibitors in Lung Cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-09, Vol.73 (17), p.5532-5543
• Main Authors: BINGBING DAI, YOO, Suk-Young, BINGLIANG FANG, ROTH, Jack A, BARTHOLOMEUSZ, Geoffrey, GRAHAM, Ryan A, MAJIDI, Mourad, SHAOYU YAN, JIERU MENG, LIN JI, COOMBES, Kevin, MINNA, John D
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antirheumatic Agents - pharmacology; Apoptosis; Auranofin - pharmacology; Biological and medical sciences; Blotting, Western; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Proliferation; Fluorescent Antibody Technique; Genes, Lethal; Glutathione - metabolism; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Immunoenzyme Techniques; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kelch-Like ECH-Associated Protein 1; Luciferases - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medical sciences; Mice; Microscopy, Fluorescence; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Staging; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Pharmacology. Drug treatments; Pneumology; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Reactive Oxygen Species - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Thioredoxin Reductase 1 - antagonists & inhibitors; Thioredoxin Reductase 1 - genetics; Thioredoxin Reductase 1 - metabolism; Tumor Cells, Cultured; Tumors; Tumors of the respiratory system and mediastinum
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-13-0712

Intrinsic resistance to agents targeting phosphoinositide 3-kinase (PI3K)/AKT pathway is one of the major challenges in cancer treatment with such agents. The objective of this study is to identify the genes or pathways that can be targeted to overcome the resistance of non-small cell lung carcinoma (NSCLC) to the AKT inhibitor MK2206, which is currently being evaluated in phase I and II clinical trials. Using a genome-wide siRNA library screening and biologic characterization, we identified that inhibition of thioredoxin reductase-1 (TXNRD1), one of the key antioxidant enzymes, with siRNAs or its inhibitor, auranofin, sensitized NSCLC cells to MK2206 treatment in vitro and in vivo. We found that simultaneous inhibition of TXNRD1 and AKT pathways induced robust reactive oxygen species production, which was involved in c-jun-NH2-kinase (JNK; MAPK8) activation and cell apoptosis. Furthermore, we found that the synthetic lethality interaction between the TXNRD1 and AKT pathways occurred through the KEAP1/NRF2 cellular antioxidant pathway. Finally, we found that synthetic lethality induced by TXNRD1 and AKT inhibitors relied on wild-type KEAP1 function. Our study indicates that targeting the interaction between AKT and TXNRD1 antioxidant pathways with MK2206 and auranofin, a U.S. Food and Drug Administration-approved drug, is a rational strategy to treat lung cancer and that KEAP1 mutation status may offer a predicative biomarker for such combination approaches.