title: DUSP1 expression induced by HDAC1 inhibition mediates gefitinib sensitivity in non-small cell lung cancers.
abstract: OBJECTIVE
  Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. Patients with NSCLC with EGFR-activating mutation benefit greatly by gefitinib, an EGFR tyrosine kinase inhibitor. However, acquired resistance limits its clinical use. Histone deacetylases (HDAC) are oncoproteins associated with cancer progression and drug resistance. Here, we disclosed that inhibition of HDAC1 induced protein phosphatase DUSP1 upregulation to overcome gefitinib-acquired resistance.
  
  
  METHODS
  The effect of HDAC1 inhibition restored gefitinib sensitivity was assessed by in vitro MTT and apoptotic assays, and in vivo xenograft and orthotopic lung cancer mouse models. Protein phosphatase array was used to detect DUSP1 expression. Immunohistochemical staining and quantitative PCR were used to analyze DUSP1 expression in clinical NSCLC specimens.
  
  
  RESULTS
  Gefitinib-resistant NSCLC cells showed HDAC1 overexpression, and its knockdown sensitized resistant cells to gefitinib in vitro and in preclinical models through DUSP1 expression. Overexpression of DUSP1 in resistant cells restored gefitinib sensitivity by inhibiting EGFR signaling and inducing apoptosis, whereas its knockdown in sensitive cells conferred gefitinib resistance. A novel HDAC inhibitor, WJ-26210-2, in combination with gefitinib upregulated DUSP1 expression to exert in vitro and in vivo synergistic effect on inactivation of EGFR signaling, growth inhibition, and apoptosis. Clinically, high DUSP1 level was correlated with delayed emergence of gefitinib-acquired resistance.
  
  
  CONCLUSIONS
  Decreased DUSP1 might be a mechanism responsible for gefitinib resistance, and DUSP1 might be a biomarker for gefitinib efficacy. HDAC1 inhibition-induced DUSP1 upregulation could be a promising strategy to overcome gefitinib-acquired resistance. Clin Cancer Res; 21(2); 428-38. ©2015 AACR.
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yun-Chieh
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan. Division of Oncology and Hematology, Department of Internal Medicine, Far-Eastern Memorial Hospital, New Taipei City, Taiwan. Department of Oncology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Yu-Chin
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Jin-Yuan
authors.initials: JY
authors.lastname: Shih
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Shi-Wei
authors.initials: SW
authors.lastname: Chao
authors.affiliation: Department of Pathology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.
authors.forename: Yih-Leong
authors.initials: YL
authors.lastname: Chang
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan. chingchowchen@ntu.edu.tw.
authors.forename: Ching-Chow
authors.initials: CC
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D011799:Quinazolines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D011799:Quinazolines; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D000077156:Gefitinib