Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Cancer Center and College of Medicine, Mayo Clinic, 200 First Street SW, Stabile Building Room st8-08 Rochester, Minnesota 55905, USA.
Department of Biochemistry and Molecular Biology, Cancer Center and College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
Nat Commun. 2016 Jul 26;7:12231. doi: 10.1038/ncomms12231.
The Zinc-finger E-box-binding Homeobox-1 (ZEB1) is a transcription factor that promotes epithelial-mesenchymal transition (EMT) and acts as an oncogene in KRAS-mutated lung cancer models. Here we report that ZEB1 exerts the opposite effect in EGFR-mutated lung cancer cells, where it suppresses growth by increasing microRNA-200 targets to antagonize ERBB3, a driver of mutant EGFR-dependent cell growth. Among these targets, NOTCH1 represses ERBB3 promoter activity and the expression of ERBB3. Furthermore, we find that EGFR inhibitor treatment, which inhibits the growth of EGFR-mutated cells, induces ZEB1. Despite its growth-inhibiting effect, EGFR inhibitor-induced ZEB1 strongly promotes EMT-dependent resistance to EGFR inhibitors partially through NOTCH1, suggesting a multifunctional role for NOTCH1 in EGFR-mutated cells. These results support a previously unrecognized genetic cell context-dependent role for ZEB1 and suggest that NOTCH1 may be a useful target for treating resistance to EGFR inhibitors, especially EMT-driven resistance.
锌指 E 盒结合同源盒 1（ZEB1）是一种转录因子，可促进上皮-间充质转化（EMT），并在 KRAS 突变型肺癌模型中作为癌基因发挥作用。在这里，我们报告 ZEB1 在 EGFR 突变型肺癌细胞中发挥相反的作用，通过增加 microRNA-200 的靶标来拮抗 ERBB3，从而抑制生长，ERBB3 是驱动突变型 EGFR 依赖性细胞生长的驱动基因。在这些靶标中，NOTCH1 抑制 ERBB3 启动子活性和 ERBB3 的表达。此外，我们发现 EGFR 抑制剂治疗（抑制 EGFR 突变型细胞的生长）可诱导 ZEB1。尽管 ZEB1 具有抑制生长的作用，但 EGFR 抑制剂诱导的 ZEB1 强烈促进 EMT 依赖性对 EGFR 抑制剂的耐药性，部分通过 NOTCH1 促进，这表明 NOTCH1 在 EGFR 突变型细胞中具有多功能作用。这些结果支持 ZEB1 以前未被认识的遗传细胞上下文依赖性作用，并表明 NOTCH1 可能是治疗 EGFR 抑制剂耐药性的有用靶点，特别是 EMT 驱动的耐药性。
