Dysfunction of epidermal growth factor receptor (EGFR) signalling plays a critical role in the oncogenesis of non–small‐cell lung cancer (NSCLC). Here, we reported the natural product, licochalcone A, exhibited a profound anti‐tumour efficacy through directly targeting EGFR signalling. Licochalcone A inhibited in vitro cell growth, colony formation and in vivo tumour growth of either wild‐type (WT) or activating mutation EGFR‐expressed NSCLC cells. Licochalcone A bound with L858R single‐site mutation, exon 19 deletion, L858R/T790M mutation and WT EGFR ex vivo, and impaired EGFR kinase activity both in vitro and in NSCLC cells. The in silico docking study further indicated that licochalcone A interacted with both WT and mutant EGFRs. Moreover, licochalcone A induced apoptosis and decreased survivin protein robustly in NSCLC cells. Mechanistically, we found that treatment with licochalcone A translationally suppressed survivin through inhibiting EGFR downstream kinases ERK1/2 and Akt. Depletion of the translation initiation complex by eIF4E knockdown effectively inhibited survivin expression. In contrast, knockdown of 4E‐BP1 showed the opposite effect and dramatically enhanced survivin protein level. Overall, our data indicate that targeting survivin might be an alternative strategy to sensitize EGFR‐targeted therapy.

中文翻译：

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甘草查耳酮 A 抑制 EGFR 信号转导并在人癌细胞中抑制 survivin 表达

表皮生长因子受体 (EGFR) 信号传导功能障碍在非小细胞肺癌 (NSCLC) 的发生中起关键作用。在这里，我们报道了天然产物甘草查尔酮 A 通过直接靶向 EGFR 信号传导而表现出深刻的抗肿瘤功效。甘草查耳酮 A 抑制野生型 (WT) 或激活突变 EGFR 表达的 NSCLC 细胞的体外细胞生长、集落形成和体内肿瘤生长。甘草查耳酮 A 与 L858R 单位点突变、外显子 19 缺失、L858R/T790M 突变和 WT EGFR 离体结合，并在体外和 NSCLC 细胞中损害 EGFR 激酶活性。计算机对接研究进一步表明，甘草查耳酮 A 与 WT 和突变 EGFR 相互作用。此外，甘草查耳酮 A 在 NSCLC 细胞中强烈诱导细胞凋亡并降低生存素蛋白。机械地，我们发现用甘草查耳酮 A 治疗通过抑制 EGFR 下游激酶 ERK1/2 和 Akt 翻译抑制存活蛋白。eIF4E 敲低对翻译起始复合物的消耗有效地抑制了生存素的表达。相比之下，4E-BP1 的敲低显示出相反的效果，并显着提高了生存素蛋白水平。总体而言，我们的数据表明靶向 survivin 可能是一种使 EGFR 靶向治疗敏感的替代策略。