title: A microRNA gene expression signature predicts response to erlotinib in epithelial cancer cell lines and targets EMT.
abstract: BACKGROUND
  Treatment with epidermal growth factor receptor (EGFR) inhibitors can result in clinical response in non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) for some unselected patients. EGFR and KRAS mutation status, amplification of EGFR, or gene expression predictors of response can forecast sensitivity to EGFR inhibition.
  
  
  METHODS
  Using an NSCLC cell line model system, we identified and characterised microRNA (miRNA) gene expression that predicts response to EGFR inhibition.
  
  
  RESULTS
  Expression of 13 miRNA genes predicts response to EGFR inhibition in cancer cell lines and tumours, and discriminates primary from metastatic tumours. Signature genes target proteins that are enriched for epithelial-to-mesenchymal transition (EMT) genes. Epithelial-to-mesenchymal transition predicts EGFR inhibitor resistance and metastatic behaviour. The EMT transcription factor, ZEB1, shows altered expression in erlotinib-sensitive NSCLC and PDAC, where many signature miRNA genes are upregulated. Ectopic expression of mir-200c alters expression of EMT proteins, sensitivity to erlotinib, and migration in lung cells. Treatment with TGFβ1 changes expression of signature miRNA and EMT proteins and modulates migration in lung cells.
  
  
  CONCLUSIONS
  From these data, we hypothesise that the tumour microenvironment elicits TGFβ1 and stimulates a miRNA gene expression program that induces resistance to anti-EGFR therapy and drives lung tumour cells to EMT, invasion, and metastasis.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, 343 Bio-Pharm Complex, University of Kentucky, Lexington, KY 40536-0082, USA.
authors: J L
authors: JL
authors: Bryant
authors: J
authors: J
authors: Britson
authors: J M
authors: JM
authors: Balko
authors: M
authors: M
authors: Willian
authors: R
authors: R
authors: Timmons
authors: A
authors: A
authors: Frolov
authors: E P
authors: EP
authors: Black
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D020869:Gene Expression Profiling; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000473:pathology*; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors