title: Chemoresistance in non-small-cell lung cancer: can multidrug resistance markers predict the response of xenograft lung cancer models to chemotherapy?
abstract: OBJECTIVE
  In chemotherapy for non-small-cell lung cancer (NSCLC), some patients seem to exhibit an intrinsic resistance or develop an acquired resistance under treatment. Results on resistance markers for possible treatment failure as shown in studies on selected lung cancer cell lines could not be completely confirmed in clinical trials. As these conflicting data require further research, we created a model between cell culture and the clinical need to study this problem.
  
  
  METHODS
  Our study was based on patient-derived NSCLC xenografts in a mouse model, which revealed a high coincidence with the original tumour. Protein and messenger RNA (mRNA) expression of known resistance markers (breast cancer resistance protein (BCRP), multidrug resistance P-glycoprotein (MDR), lung cancer-related protein (LRP) and multidrug resistance protein 1 (MRP1)) were analysed by real-time polymerase chain reaction (PCR) and immunoblotting in 24 xenografts. Chemosensitivity to etoposide, carboplatin, gemcitabine, paclitaxel, cetuximab and erlotinib was determined in in vivo xenograft experiments and compared with the protein and mRNA expression of the multidrug resistance markers.
  
  
  RESULTS
  With the exception of a single correlation between chemosensitivity and mRNA expression of etoposide and bcrp (mRNA expression of BCRP), we found no significant correlation between the response rates and protein- and mRNA expression levels in our 24 xenografts. The present results indicate that in vivo expression levels of multidrug resistance proteins and their mRNAs may not play a comparable role in chemoresistance of NSCLC, as pointed out in selected tumour cell lines.
  
  
  CONCLUSIONS
  Patient-derived xenografts allow detailed investigation of therapy-related markers and their dynamic regulation in a well-standardised and clinically related way. As a consequence of our investigations, we regard multidrug resistance to be a multifactorial phenomenon, in which more factors than the markers analysed by the present study may be involved.
authors.affiliation: Department of Thoracic Surgery, ELK Berlin Chest Hospital, Berlin, Germany. johannes.merk@elk-berlin.de
authors.forename: Johannes
authors.initials: J
authors.lastname: Merk
authors.forename: Jana
authors.initials: J
authors.lastname: Rolff
authors.forename: Cornelia
authors.initials: C
authors.lastname: Dorn
authors.forename: Gunda
authors.initials: G
authors.lastname: Leschber
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017024:Chemotherapy, Adjuvant; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm