Xiaobo Cao, Majidi Mourad, Feng Meng, Shao Ruping, Wang Jing, Zhao Yang, Baladandayuthapani Veerabhadran, Song Juhee, Fang Bingliang, Ji Lin, Mehran Reza, Roth Jack A
Section of Thoracic Molecular Oncology, Department of Thoracic and Cardiovascular Surgery, University of Texas (UT) MD Anderson Cancer Center, Houston, TX, USA.
Department of Bioinfomatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA.
Sci Rep. 2016 Nov 15;6:35741. doi: 10.1038/srep35741.
Expression of the TUSC2/FUS1 tumor suppressor gene in TUSC2 deficient EGFR wildtype lung cancer cells increased sensitivity to erlotinib. Microarray mRNA expression analysis of TUSC2 inducible lung cancer cells treated with erlotinib uncovered defects in the response to oxidative stress suggesting that increasing reactive oxygen species (ROS) would enhance therapeutic efficacy. Addition of the thioredoxin reductase 1 inhibitor (TXNRD1) auranofin (AF) to NSCLC cells treated with combination of TUSC2 forced expression with erlotinib increased tumor cell apoptosis and inhibited colony formation. TXNRD1 overexpression rescued tumors from AF-TUSC2-erlotinib induced apoptosis. Neutralizing ROS with nordihydroguaiaretic acid (NDGA) abrogated cell death induced by AF-TUSC2-erlotinib, indicating a regulatory role for ROS in the efficacy of the three drug combination. Isobologram-based statistical analysis of this combination demonstrated superior synergism, compared with each individual treatment at lower concentrations. In NSCLC tumor xenografts, tumor growth was markedly inhibited and animal survival was prolonged over controls by AF-TUSC2-erlotinib. Microarray mRNA expression analysis uncovered oxidative stress and DNA damage gene signatures significantly upregulated by AF-TUSC2-erlotinib compared to TUSC2-erlotinib. Pathway analysis showed the highest positive z-score for the NRF2-mediated oxidative stress response. Taken together these findings show that the combination of TUSC2-erlotinib induces additional novel vulnerabilities that can be targeted with AF.
TUSC2/FUS1肿瘤抑制基因在TUSC2缺陷的表皮生长因子受体（EGFR）野生型肺癌细胞中的表达增加了对厄洛替尼的敏感性。对用厄洛替尼处理的TUSC2诱导型肺癌细胞进行微阵列mRNA表达分析，发现其对氧化应激反应存在缺陷，这表明增加活性氧（ROS）将增强治疗效果。将硫氧还蛋白还原酶1抑制剂（TXNRD1）金诺芬（AF）添加到用TUSC2强制表达与厄洛替尼联合处理的非小细胞肺癌（NSCLC）细胞中，可增加肿瘤细胞凋亡并抑制集落形成。TXNRD1过表达可使肿瘤免受AF-TUSC2-厄洛替尼诱导的凋亡。用去甲二氢愈创木酸（NDGA）中和ROS可消除AF-TUSC2-厄洛替尼诱导的细胞死亡，表明ROS在三种药物联合疗效中起调节作用。基于等效线图的该联合用药统计分析表明，与较低浓度下的每种单独治疗相比，具有更强的协同作用。在NSCLC肿瘤异种移植模型中，AF-TUSC2-厄洛替尼可显著抑制肿瘤生长并延长动物生存期。微阵列mRNA表达分析发现，与TUSC2-厄洛替尼相比，AF-TUSC2-厄洛替尼可显著上调氧化应激和DNA损伤基因特征。通路分析显示NRF2介导的氧化应激反应的正z评分最高。综上所述，这些发现表明TUSC2-厄洛替尼联合用药可诱导额外的新弱点，AF可针对这些弱点发挥作用。
