JUN-Mediated Downregulation of EGFR Signaling Is Associated with Resistance to Gefitinib in EGFR-mutant NSCLC Cell Lines

Mutations or deletions in exons 18-21 in the ) are present in approximately 15% of tumors in patients with non-small cell lung cancer (NSCLC). They lead to activation of the EGFR kinase domain and sensitivity to molecularly targeted therapeutics aimed at this domain (gefitinib or erlotinib). These d...

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Published in:	Molecular cancer therapeutics Vol. 16; no. 8; pp. 1645 - 1657
Main Authors:	Kani, Kian, Garri, Carolina, Tiemann, Katrin, Malihi, Paymaneh D, Punj, Vasu, Nguyen, Anthony L, Lee, Janet, Hughes, Lindsey D, Alvarez, Ruth M, Wood, Damien M, Joo, Ah Young, Katz, Jonathan E, Agus, David B, Mallick, Parag
Format:	Journal Article
Language:	English
Published:	United States American Association for Cancer Research Inc 01-08-2017
Subjects:	Activation Adenocarcinoma Cancer Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - genetics Cell Line, Tumor Chromatin - metabolism Correlation coefficient Correlation coefficients Down-Regulation - drug effects Drug Resistance, Neoplasm - drug effects Drugs Epidermal growth factor receptors Exons Gefitinib Gene expression Humans Kinases Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - genetics Mutation Mutation - genetics Non-small cell lung carcinoma Patients Phenotype Phosphorylation - drug effects Protein Binding - drug effects Protein-tyrosine kinase Proteomics Proto-Oncogene Proteins c-jun - metabolism Quinazolines - pharmacology Quinazolines - therapeutic use Receptor, Epidermal Growth Factor - metabolism Signal Transduction - drug effects Signaling Tumors Tyrosine Up-Regulation - drug effects
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Summary:	Mutations or deletions in exons 18-21 in the ) are present in approximately 15% of tumors in patients with non-small cell lung cancer (NSCLC). They lead to activation of the EGFR kinase domain and sensitivity to molecularly targeted therapeutics aimed at this domain (gefitinib or erlotinib). These drugs have demonstrated objective clinical response in many of these patients; however, invariably, all patients acquire resistance. To examine the molecular origins of resistance, we derived a set of gefitinib-resistant cells by exposing lung adenocarcinoma cell line, HCC827, with an activating mutation in the EGFR tyrosine kinase domain, to increasing gefitinib concentrations. Gefitinib-resistant cells acquired an increased expression and activation of JUN, a known oncogene involved in cancer progression. Ectopic overexpression of JUN in HCC827 cells increased gefitinib IC from 49 nmol/L to 8 μmol/L ( < 0.001). Downregulation of JUN expression through shRNA resensitized HCC827 cells to gefitinib (IC from 49 nmol/L to 2 nmol/L; < 0.01). Inhibitors targeting JUN were 3-fold more effective in the gefitinib-resistant cells than in the parental cell line ( < 0.01). Analysis of gene expression in patient tumors with EGFR-activating mutations and poor response to erlotinib revealed a similar pattern as the top 260 differentially expressed genes in the gefitinib-resistant cells (Spearman correlation coefficient of 0.78, < 0.01). These findings suggest that increased JUN expression and activity may contribute to gefitinib resistance in NSCLC and that JUN pathway therapeutics merit investigation as an alternate treatment strategy. .
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1535-7163 1538-8514
DOI:	10.1158/1535-7163.MCT-16-0564