The TGFβ-miR200-Mig6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors

摘要: While specific mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) identify tumors that are responsive to EGFR inhibitors (TKIs), these genetic alterations present only a minority patients. Patients with expressing wild-type (wt) lack reliable predictive markers their clinical response TKIs. Although epithelial-mesenchymal transition (EMT) has been inversely correlated cancers EGFR-targeted therapy, precise molecular mechanisms underlying this association have not defined and no EMT-associated biomarker benefit identified. Here we show during transforming factor-β (TGFβ)-mediated EMT, inhibition microRNAs 200 (miR200) family results upregulated expression mitogen-inducible gene 6 (Mig6), negative regulator EGFR. The Mig6-mediated reduction occurs concomitantly TGFβ-induced switch tumor cells an AKT-activated EGFR-independent state. In panel 25 cancer cell lines different tissue origins, find ratio levels Mig6 miR200c is highly EMT resistance erlotinib. Analyses primary xenografts patient-derived lung pancreatic carrying wild type showed Mig6(mRNA)/miR200 was erlotinib vivo. Our data demonstrate TGFβ-miR200-Mig6 network orchestrates induces inhibitors, low miR200 as promising