title: Inhibiting proliferation of gefitinib-resistant, non-small cell lung cancer.
abstract: OBJECTIVE
  Sensitivity to a tyrosine kinase inhibitor (TKI) is correlated with the presence of somatic mutations that affect the kinase domain of epidermal growth factor receptor (EGFR). Development of resistance to TKI is a major therapeutic problem in non-small cell lung cancer (NSCLC). Aim of this study is to identify agents that can overcome TKI resistance in NSCLC.
  
  
  METHODS
  We used a carefully selected panel of 12 NSCLC cell lines to address this clinical problem. Initially, the cell lines were treated with a variety of 10 compounds. Cellular proliferation was measured via MTT assay. We then focused on the gefitinib-resistant, EGFR mutant cell lines [H1650: exon 19 and PTEN mutations; and H1975: exons 20 (T790M) and 21 (L858R)] to identify agents that could overcome TKI resistance.
  
  
  RESULTS
  Both 17-DMAG (Hsp90 inhibitor) and belinostat (histone deacetylase inhibitor, HDACi) effectively decreased the growth of almost all NSCLC lines. Also, belinostat markedly decreased the expression of EGFR and phospho-Akt in the cells. Combination of 17-DMAG and belinostat synergistically inhibited in vitro proliferation of these cells. Furthermore, both agents and their combination almost completely prevented TKI-resistant tumor formation (EGFR T790M mutation) in a xenograft model.
  
  
  CONCLUSIONS
  These results suggest that the combination of 17-DMAG and belinostat should be examined in a clinical trial for TKI-resistant NSCLC cell.
authors.affiliation: Cancer Science Institute, National University of Singapore, Singapore, Singapore. makotosudo@live.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Sudo
authors.forename: Tan Min
authors.initials: TM
authors.lastname: Chin
authors.forename: Seiichi
authors.initials: S
authors.lastname: Mori
authors.forename: Ngan B
authors.initials: NB
authors.lastname: Doan
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Said
authors.forename: Makoto
authors.initials: M
authors.lastname: Akashi
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics; D000077156:Gefitinib; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D006877:Hydroxamic Acids; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D013449:Sulfonamides; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; C487081:belinostat; D000077156:Gefitinib