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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.

A genetic cell context-dependent role for ZEB1 in lung cancer