A microRNA gene expression signature predicts response to erlotinib in epithelial cancer cell lines and targets EMT

• Published in: British journal of cancer Vol. 106; no. 1; pp. 148 - 156
• Main Authors: Bryant, J L, Britson, J, Balko, J M, Willian, M, Timmons, R, Frolov, A, Black, E P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03-01-2012; Nature Publishing Group
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Biological and medical sciences; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Line, Tumor; Cells; Drug Resistance; Epidemiology; Epidermal growth factor; Epithelial-Mesenchymal Transition - drug effects; Erlotinib Hydrochloride; Gene expression; Gene Expression Profiling; General aspects; Humans; Lung cancer; Medical research; Medical sciences; Metastasis; MicroRNAs; MicroRNAs - genetics; Molecular Diagnostics; Molecular Medicine; Neoplasms, Glandular and Epithelial - pathology; Oncology; Pancreatic cancer; Pharmacology. Drug treatments; Proteins; Quinazolines - pharmacology; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Tumors; United States > US; targeted therapy; invasion; biomarker; metastasis; Antineoplastic agent; RNA interference; Targeted therapy; Quinazoline derivatives; Lung cancer; Biological marker; Metastasis; non-small cell lung carcinoma; Cancerology; Established cell line; Genetics; Bronchus disease; Protein-tyrosine kinase; Human; Lung disease; Enzyme; Tyrosine kinase inhibitor; Respiratory disease; Transferases; Treatment efficiency; Micro RNA; Enzyme inhibitor; Malignant tumor; Gene expression; Gene silencing; Treatment; Erlotinib; Epithelial mesenchymal transition; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2011.465

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 TGF
β
1 changes expression of signature miRNA and EMT proteins and modulates migration in lung cells.
Conclusion:
From these data, we hypothesise that the tumour microenvironment elicits TGF
β
1 and stimulates a miRNA gene expression program that induces resistance to anti-EGFR therapy and drives lung tumour cells to EMT, invasion, and metastasis.