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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

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 degre...

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Autores principales: Zhang, Xu-chao, Zhang, Jingchuan, Li, Ming, Huang, Xiao-sui, Yang, Xue-ning, Zhong, Wen-zhao, Xie, Liang, Zhang, Lin, Zhou, Minhua, Gavine, Paul, Su, Xinying, Zheng, Li, Zhu, Guanshan, Zhan, Ping, Ji, Qunsheng, Wu, Yi-long
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716998/
https://www.ncbi.nlm.nih.gov/pubmed/23842453
http://dx.doi.org/10.1186/1479-5876-11-168
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author Zhang, Xu-chao
Zhang, Jingchuan
Li, Ming
Huang, Xiao-sui
Yang, Xue-ning
Zhong, Wen-zhao
Xie, Liang
Zhang, Lin
Zhou, Minhua
Gavine, Paul
Su, Xinying
Zheng, Li
Zhu, Guanshan
Zhan, Ping
Ji, Qunsheng
Wu, Yi-long
author_facet Zhang, Xu-chao
Zhang, Jingchuan
Li, Ming
Huang, Xiao-sui
Yang, Xue-ning
Zhong, Wen-zhao
Xie, Liang
Zhang, Lin
Zhou, Minhua
Gavine, Paul
Su, Xinying
Zheng, Li
Zhu, Guanshan
Zhan, Ping
Ji, Qunsheng
Wu, Yi-long
author_sort Zhang, Xu-chao
collection PubMed
description 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.
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spelling pubmed-37169982013-07-21 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 Zhang, Xu-chao Zhang, Jingchuan Li, Ming Huang, Xiao-sui Yang, Xue-ning Zhong, Wen-zhao Xie, Liang Zhang, Lin Zhou, Minhua Gavine, Paul Su, Xinying Zheng, Li Zhu, Guanshan Zhan, Ping Ji, Qunsheng Wu, Yi-long J Transl Med Research 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. BioMed Central 2013-07-10 /pmc/articles/PMC3716998/ /pubmed/23842453 http://dx.doi.org/10.1186/1479-5876-11-168 Text en Copyright © 2013 Zhang et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Zhang, Xu-chao
Zhang, Jingchuan
Li, Ming
Huang, Xiao-sui
Yang, Xue-ning
Zhong, Wen-zhao
Xie, Liang
Zhang, Lin
Zhou, Minhua
Gavine, Paul
Su, Xinying
Zheng, Li
Zhu, Guanshan
Zhan, Ping
Ji, Qunsheng
Wu, Yi-long
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
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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716998/
https://www.ncbi.nlm.nih.gov/pubmed/23842453
http://dx.doi.org/10.1186/1479-5876-11-168
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