title: Establishment of patient-derived non-small cell lung cancer xenograft models with genetic aberrations within EGFR, KRAS and FGFR1: useful tools for preclinical studies of targeted therapies.
abstract: BACKGROUND
  Patient-derived tumor xenograft models have been established and increasingly used for preclinical studies of targeted therapies in recent years. However, patient-derived non-small cell lung cancer (NSCLC) xenograft mouse models are relatively few in number and are limited in their degree of genetic characterization and validation. In this study, we aimed to establish a variety of patient-derived NSCLC models and characterize these for common genetic aberrations to provide more informative models for preclinical drug efficacy testing.
  
  
  METHODS
  NSCLC tissues from thirty-one patients were collected and implanted into immunodeficient mice. Established xenograft models were characterized for common genetic aberrations, including detection of gene mutations within EGFR and KRAS, and genetic amplification of FGFR1 and cMET. Finally, gefitinib anti-tumor efficacy was tested in these patient-derived NSCLC xenograft models.
  
  
  RESULTS
  Ten passable patient-derived NSCLC xenograft models were established by implantation of NSCLC specimens of thirty-one patients into immunodeficient mice. Genetic aberrations were detected in six of the models, including one model with an EGFR activating mutation (Exon19 Del), one model with KRAS mutation, one model with both KRAS mutation and cMET gene amplification, and three models with FGFR1 amplification. Anti-tumor efficacy studies using gefitinib demonstrated that the EGFR activating mutation model had superior sensitivity and that the KRAS mutation models were resistant to gefitinib. The range of gefitinib responses in the patient-derived NSCLC xenograft models were consistent with the results reported from clinical trials. Furthermore, we observed that patient-derived NSCLC models with FGFR1 gene amplification were insensitive to gefitinib treatment.
  
  
  CONCLUSIONS
  Ten patient-derived NSCLC xenograft models were established containing a variety of genetic aberrations including EGFR activating mutation, KRAS mutation, and FGFR1 and cMET amplification. Gefitinib anti-tumor efficacy in these patient-derived NSCLC xenografts containing EGFR and KRAS mutation was consistent with the reported results from previous clinical trials. Thus, data from our panel of patient-derived NSCLC xenograft models confirms the utility of these models in furthering our understanding of this disease and aiding the development of personalized therapies for NSCLC patients.
authors.affiliation: Medical Research Center of Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangdong Lung Cancer Institute Guangzhou 510080, PR China.
authors.forename: Xu-chao
authors.initials: XC
authors.lastname: Zhang
authors.forename: Jingchuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Xiao-sui
authors.initials: XS
authors.lastname: Huang
authors.forename: Xue-ning
authors.initials: XN
authors.lastname: Yang
authors.forename: Wen-zhao
authors.initials: WZ
authors.lastname: Zhong
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Minhua
authors.initials: M
authors.lastname: Zhou
authors.forename: Paul
authors.initials: P
authors.lastname: Gavine
authors.forename: Xinying
authors.initials: X
authors.lastname: Su
authors.forename: Li
authors.initials: L
authors.lastname: Zheng
authors.forename: Guanshan
authors.initials: G
authors.lastname: Zhu
authors.forename: Ping
authors.initials: P
authors.lastname: Zhan
authors.forename: Qunsheng
authors.initials: Q
authors.lastname: Ji
authors.forename: Yi-long
authors.initials: YL
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D011905:Genes, ras; D014644:Genetic Variation; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D066246:ErbB Receptors; C496348:FGFR1 protein, human; D019859:Proto-Oncogene Proteins c-met; D051496:Receptor, Fibroblast Growth Factor, Type 1; D018631:ras Proteins; D000077156:Gefitinib