Constitutively activated STAT3 plays a critical role in non–small cell lung carcinoma (NSCLC) progression by mediating proliferation and survival. STAT3 activation in normal cells is transient, making it an attractive target for NSCLC therapy. The therapeutic potential of blocking STAT3 in NSCLC was assessed utilizing a decoy approach by ligating a double-stranded 15-mer oligonucleotide that corresponds to the STAT3 response element of STAT3-target genes, to produce a cyclic STAT3 decoy (CS3D). The decoy was evaluated using NSCLC cells containing either wild-type EGFR (201T) or mutant EGFR with an additional EGFRi resistance mutation (H1975). These cells are resistant to EGFR inhibitors and require an alternate therapeutic approach. CS3D activity was compared with an inactive cyclic control oligonucleotide (CS3M) that differs by a single base pair, rendering it unable to bind to STAT3 protein. Transfection of 0.3 μmol/L of CS3D caused a 50% inhibition in proliferation in 201T and H1975 cells, relative to CS3M, and a 2-fold increase in apoptotic cells. Toxicity was minimal in normal cells. CS3D treatment caused a significant reduction of mRNA and protein expression of the STAT3 target gene c-Myc and inhibited colony formation by 70%. The active decoy decreased the nuclear pool of STAT3 compared with the mutant. In a xenograft model, treatments with CS3D (5 mg/kg) caused a potent 96.5% and 81.7% reduction in tumor growth in 201T (P < 0.007) and H1975 models (P < 0.0001), respectively, and reduced c-Myc and p-STAT3 proteins. Targeting STAT3 with the cyclic decoy could be an effective therapeutic strategy for NSCLC. Mol Cancer Ther; 17(9); 1917–26. ©2018 AACR.

中文翻译：

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STAT3 环状诱饵在非小细胞肺癌中表现出强大的抗肿瘤作用

持续激活的 STAT3 通过介导增殖和存活在非小细胞肺癌 (NSCLC) 进展中发挥关键作用。正常细胞中的 STAT3 激活是短暂的，这使其成为 NSCLC 治疗的有吸引力的靶点。利用诱饵方法评估在 NSCLC 中阻断 STAT3 的治疗潜力，通过连接与 STAT3 靶基因的 STAT3 反应元件相对应的双链 15 聚体寡核苷酸，产生环状 STAT3 诱饵 (CS3D)。使用含有野生型 EGFR (201T) 或带有额外 EGFRi 抗性突变 (H1975) 的突变 EGFR 的 NSCLC 细胞评估诱饵。这些细胞对 EGFR 抑制剂具有耐药性，需要替代治疗方法。将 CS3D 活性与无活性的环状控制寡核苷酸 (CS3M) 进行比较，后者仅存在一个碱基对的差异，使其无法与 STAT3 蛋白结合。转染0.3 μmol/L的CS3D，相对于CS3M，201T和H1975细胞的增殖抑制50%，凋亡细胞增加2倍。对正常细胞的毒性很小。CS3D 处理导致 STAT3 靶基因 c-Myc 的 mRNA 和蛋白表达显着降低，并抑制集落形成 70%。与突变体相比，活性诱饵减少了 STAT3 的核池。在异种移植模型中，CS3D (5 mg/kg) 治疗使 201T (P < 0.007) 和 H1975 模型 (P < 0.0001) 的肿瘤生长分别有效减少 96.5% 和 81.7%，并减少 c-Myc 和p-STAT3 蛋白。用环状诱饵靶向 STAT3 可能是 NSCLC 的有效治疗策略。摩尔癌症治疗；17(9)；1917–26。©2018 AACR。