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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.

Zhang XC, Zhang J, Li M, Huang XS, Yang XN, Zhong WZ, Xie L, Zhang L, Zhou M, Gavine P, Su X, Zheng L, Zhu G, Zhan P, Ji Q, Wu YL - J Transl Med (2013)

Bottom Line: Patient-derived tumor xenograft models have been established and increasingly used for preclinical studies of targeted therapies in recent years.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Medical Research Center of Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangdong Lung Cancer Institute Guangzhou 510080, PR China.

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.

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Representative pictures of FISH imaging on patient-derived NSCLC xenograft models L004, L023, L104, L121, L133 with matched human primary tumor tissues.FGFR and cMET gene amplifications were detected in models L121/L133, and L023, respectively. Non-FGFR gene and non-cMET gene amplification were detected in models L104 and L004, respectively.
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Figure 2: Representative pictures of FISH imaging on patient-derived NSCLC xenograft models L004, L023, L104, L121, L133 with matched human primary tumor tissues.FGFR and cMET gene amplifications were detected in models L121/L133, and L023, respectively. Non-FGFR gene and non-cMET gene amplification were detected in models L104 and L004, respectively.

Mentions: Mutation of EGFR, KRAS and gene amplification of FGFR1 and cMET were screened for in all 31 patient samples and ten established xenograft samples. One model with an EGFR activating mutation (Exon19Del) and two models with KRAS mutations (G12S and Q61H) were identified in the ten patient-derived NSCLC models and their corresponding patient NSCLC tissues (Table 3). Furthermore, gene amplification of FGFR1 was detected in additional three models and cMET in one model (KRAS mutant background). Again, these genetic aberrations were identified in both patient-derived NSCLC models and their corresponding patient NSCLC tissues (Table 3 and Figure 2), with the exception of one model (L123) which lacked sufficient patient LC tissue for analysis.


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 XC, Zhang J, Li M, Huang XS, Yang XN, Zhong WZ, Xie L, Zhang L, Zhou M, Gavine P, Su X, Zheng L, Zhu G, Zhan P, Ji Q, Wu YL - J Transl Med (2013)

Representative pictures of FISH imaging on patient-derived NSCLC xenograft models L004, L023, L104, L121, L133 with matched human primary tumor tissues.FGFR and cMET gene amplifications were detected in models L121/L133, and L023, respectively. Non-FGFR gene and non-cMET gene amplification were detected in models L104 and L004, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3716998&req=5

Figure 2: Representative pictures of FISH imaging on patient-derived NSCLC xenograft models L004, L023, L104, L121, L133 with matched human primary tumor tissues.FGFR and cMET gene amplifications were detected in models L121/L133, and L023, respectively. Non-FGFR gene and non-cMET gene amplification were detected in models L104 and L004, respectively.
Mentions: Mutation of EGFR, KRAS and gene amplification of FGFR1 and cMET were screened for in all 31 patient samples and ten established xenograft samples. One model with an EGFR activating mutation (Exon19Del) and two models with KRAS mutations (G12S and Q61H) were identified in the ten patient-derived NSCLC models and their corresponding patient NSCLC tissues (Table 3). Furthermore, gene amplification of FGFR1 was detected in additional three models and cMET in one model (KRAS mutant background). Again, these genetic aberrations were identified in both patient-derived NSCLC models and their corresponding patient NSCLC tissues (Table 3 and Figure 2), with the exception of one model (L123) which lacked sufficient patient LC tissue for analysis.

Bottom Line: Patient-derived tumor xenograft models have been established and increasingly used for preclinical studies of targeted therapies in recent years.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Medical Research Center of Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangdong Lung Cancer Institute Guangzhou 510080, PR China.

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.

Show MeSH
Related in: MedlinePlus