TY - JOUR
T1 - KEAP1-dependent synthetic lethality induced by AKT and TXNRD1 inhibitors in lung cancer
AU - Dai, Bingbing
AU - Yoo, Suk Young
AU - Bartholomeusz, Geoffrey
AU - Graham, Ryan A.
AU - Majidi, Mourad
AU - Yan, Shaoyu
AU - Meng, Jieru
AU - Ji, Lin
AU - Coombes, Kevin
AU - Minna, John D.
AU - Fang, Bingliang
AU - Roth, Jack A.
PY - 2013/9/1
Y1 - 2013/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84883471209&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883471209&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-13-0712
DO - 10.1158/0008-5472.CAN-13-0712
M3 - Article
C2 - 23824739
AN - SCOPUS:84883471209
SN - 0008-5472
VL - 73
SP - 5532
EP - 5543
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -