title: Identification of plasma microRNA profiles for primary resistance to EGFR-TKIs in advanced non-small cell lung cancer (NSCLC) patients with EGFR activating mutation.
abstract: BACKGROUND
  EGFR mutation is a strong predictor of efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) therapy in advanced non-small cell lung cancer (NSCLC). However, around 20-30 % of EGFR-mutated cases showed no response to EGFR-TKIs, suggesting that other determinants beyond EGFR mutation likely exist. This study analyzed the role of microRNAs (miRNAs) in primary resistance to EGFR-TKIs in advanced NSCLC patients with EGFR mutation.
  
  
  METHODS
  Training group: 20 advanced NSCLC patients with EGFR 19 deletion treated with first-line EGFR-TKIs were enrolled; half of them had dramatic responses while the other half had primary resistance. Matched plasma samples were collected for miRNA profiling using TaqMan low-density array (TLDA). Bioinformatics analyses were used to identify related miRNAs possibly accounted for resistance. Testing group: Quantitative reverse transcriptase PCR (qRT-PCR) was employed to detect the level of miRNA with significant differential expression in the training set. Validation group: Another cohort with EGFR 19 deletion mutations, who had dramatically different responses to EGFR-TKI, was used to validate the difference of miRNA expression between the sensitive and resistant groups using RT-PCR.
  
  
  RESULTS
  Training group: 153 miRNAs were found to be differentially expressed between the sensitive and resistant groups. Potential target genes were predicted with a target scan database. Twelve differentially expressed miRNAs were selected for the analysis because of their known roles in tumorigenesis of lung cancer, resistance to drugs, and regulation of EGFR pathway. Training group: three out of the 12 miRNAs (miR-21, AmiR-27a, and miR-218) were verified to have significantly higher expression (P miR-21 = 0.004, P miR-27a = 0.009, P miR-218 = 0.041, respectively) in the resistant group compared to the sensitive group. Validation group: The expression levels of these three miRNAs were validated to be significantly different (P = 0.011, 0.011, 0.026, respectively) in the validation cohort (n = 34).
  
  
  CONCLUSIONS
  Higher expression levels of miR-21, AmiR-27a, and miR-218 detected in this study suggest potential roles of these miRNAs in primary resistance to EGFR-TKI in advanced NSCLC patients with EGFR exon 19 deletion mutations. These findings need to be further confirmed in a study with a larger sample size.
authors.affiliation: The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China.
authors.forename: Shuhang
authors.initials: S
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Su
authors.affiliation: The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Bai
authors.affiliation: The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Duan
authors.affiliation: The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China.
authors.forename: Tongtong
authors.initials: T
authors.lastname: An
authors.affiliation: The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China.
authors.forename: Minglei
authors.initials: M
authors.lastname: Zhuo
authors.affiliation: The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Wang
authors.affiliation: The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China.
authors.forename: Meina
authors.initials: M
authors.lastname: Wu
authors.affiliation: The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China.
authors.forename: Zhenxiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Thoracic Medical Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, 100036, Beijing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhu
authors.affiliation: The Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing, China. wangjie_cc@yahoo.com.|Department of Bioscience and Nutrition, Novum, Karolinska Institute, 141 83, Huddinge, Sweden. wangjie_cc@yahoo.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D035683:MicroRNAs / Q000097:blood*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017384:Sequence Deletion
chemical_list: D000970:Antineoplastic Agents; C524940:MIRN21 microRNA, human; C547471:MIRN218 microRNA, human; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors