KEAP1-dependent synthetic lethality induced by AKT and TXNRD1 inhibitors in lung cancer

Bingbing Dai, Suk Young Yoo, Geoffrey Bartholomeusz, Ryan A. Graham, Mourad Majidi, Shaoyu Yan, Jieru Meng, Lin Ji, Kevin Coombes, John D. Minna, Bingliang Fang, Jack A. Roth

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34 Scopus citations

Abstract

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 identi fied that inhibition of thioredoxin reductase-1 (TXNRD1), one of the key antioxidant enzymes, with siRNAs or its inhibitor, aurano fin, 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 aurano fin, 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.

Original languageEnglish (US)
Pages (from-to)5532-5543
Number of pages12
JournalCancer Research
Volume73
Issue number17
DOIs
Publication statusPublished - Sep 1 2013

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Dai, B., Yoo, S. Y., Bartholomeusz, G., Graham, R. A., Majidi, M., Yan, S., ... Roth, J. A. (2013). KEAP1-dependent synthetic lethality induced by AKT and TXNRD1 inhibitors in lung cancer. Cancer Research, 73(17), 5532-5543. https://doi.org/10.1158/0008-5472.CAN-13-0712