KEAP1-dependent synthetic lethality induced by AKT and TXNRD1 inhibitors in lung cancer.
KEAP1-dependent synthetic lethality induced by AKT and TXNRD1 inhibitors in lung cancer.
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DOI：
10.1158/0008-5472.can-13-0712
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发表时间：
2013-09-01
期刊：
影响因子：
11.2
通讯作者：
Roth JA
中科院分区：
文献类型：
--
作者：
Dai B;Yoo SY;Bartholomeusz G;Graham RA;Majidi M;Yan S;Meng J;Ji L;Coombes K;Minna JD;Fang B;Roth JA
对靶向磷脂酰肌醇-3激酶(PI3K)/AKT通路的药物的内在耐药性是此类药物治疗癌症的主要挑战之一。本研究的目的是确定可以靶向克服非小细胞肺癌对AKT抑制剂MK2206耐药的基因或途径，MK2206目前正在I期和II期临床试验中进行评估。利用全基因组小干扰RNA （siRNA）文库筛选和生物学特性鉴定，我们发现siRNA或其抑制剂Auranofin抑制关键抗氧化酶之一硫氧还蛋白还原酶-1 (TXNRD1)，在体外和体内使非小细胞肺癌细胞对MK2206治疗敏感。我们发现，同时抑制TXNRD1和AKT通路可诱导活性氧（ROS）的产生，这参与了c-Jun n -末端激酶（JNK, MAPK8）的激活和细胞凋亡。此外，我们发现TXNRD1与AKT通路之间的合成致死性相互作用是通过KEAP1/NRF2细胞抗氧化途径发生的。最后，我们发现TXNRD1和AKT抑制剂诱导的合成致死性依赖于野生型KEAP1功能。我们的研究表明，靶向AKT和TXNRD1抗氧化途径与MK2206和Auranofin （FDA批准的药物）的相互作用是治疗肺癌的合理策略，KEAP1突变状态可能为这种联合方法提供预测性生物标志物。
Intrinsic resistance to agents targeting phosphatidylinositol-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 cancer to the AKT inhibitor, MK2206, which is currently being evaluated in phase I and II clinical trials. Using a genome-wide small interfering RNA (siRNA) library screening and biological characterization we identified that inhibition of Thioredoxin Reductase-1 (TXNRD1), one of the key anti-oxidant enzymes, with siRNAs or its inhibitor, Auranofin, sensitized non-small cell lung cancer cells to MK2206 treatment in vitro and in vivo. We found that simultaneous inhibition of TXNRD1 and AKT pathways induced robust reactive oxygen species (ROS) production, which was involved in c-Jun N-terminal 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. Lastly, 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 FDA approved drug, is a rational strategy to treat lung cancer and that KEAP1 mutation status may offer a predicative biomarker for such combination approaches.