title: Baseline gene expression predicts sensitivity to gefitinib in non-small cell lung cancer cell lines.
abstract: Tyrosine kinase inhibitors (TKI) of the epidermal growth factor receptor (EGFR) produce objective responses in a minority of patients with advanced-stage non-small cell lung cancer (NSCLC), and about half of all treated patients progress within 6 weeks of instituting therapy. Because the target of these agents is known, it should be possible to develop biological predictors of response, but EGFR protein levels have not been proven useful as a predictor of TKI response in patients and the mechanism of primary resistance is unclear. We used microarray gene expression profiling to uncover a pattern of gene expression associated with sensitivity to EGFR-TKIs by comparing NSCLC cell lines that were either highly sensitive or highly resistant to gefitinib. This sensitivity-associated expression profile was used to predict gefitinib sensitivity in a panel of NSCLC cell lines with known gene expression profiles but unknown gefitinib sensitivity. Gefitinib sensitivity was then determined for members of this test panel, and the microarray-based sensitivity prediction was correct in eight of nine NSCLC cell lines. Gene and protein expression differences were confirmed with a combination of quantitative reverse transcription-PCR, flow cytometry, and immunohistochemistry. This gene expression pattern related to gefitinib sensitivity was independent from sensitivity associated with EGFR mutations. Several genes associated with sensitivity encode proteins involved in HER pathway signaling or pathways that interrelate to the HER signaling pathway. Some of these genes could be targets of pharmacologic interventions to overcome primary resistance.
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, C272, Denver, 80262, USA. chris.coldren@uchsc.edu
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Coldren
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Helfrich
authors.forename: Samir E
authors.initials: SE
authors.lastname: Witta
authors.forename: Michio
authors.initials: M
authors.lastname: Sugita
authors.forename: Razvan
authors.initials: R
authors.lastname: Lapadat
authors.forename: Chan
authors.initials: C
authors.lastname: Zeng
authors.forename: Anna
authors.initials: A
authors.lastname: Barón
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.forename: Mark W
authors.initials: MW
authors.lastname: Geraci
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D015820:Cadherins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D016000:Cluster Analysis; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000235:genetics; D005434:Flow Cytometry / Q000379:methods; D000077156:Gefitinib; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000145:classification; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy*; D005810:Multigene Family; D009154:Mutation / Q000187:drug effects; D016133:Polymerase Chain Reaction / Q000379:methods; D047428:Protein Kinase Inhibitors; D020543:Proteome / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000627:therapeutic use*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D018631:ras Proteins
chemical_list: D000970:Antineoplastic Agents; D015820:Cadherins; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D020543:Proteome; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000077156:Gefitinib