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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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In vivo growth curves of patient-derived NSCLC xenograft models. Tumor growth curves of patient-derived NSCLC xenograft models. The models were established subcutaneously and tumor growth curves in passable and stable xenograft models were generated by tumor measurement between passage 3–5 (F3-5). Media of tumor volume was showed.
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Figure 1: In vivo growth curves of patient-derived NSCLC xenograft models. Tumor growth curves of patient-derived NSCLC xenograft models. The models were established subcutaneously and tumor growth curves in passable and stable xenograft models were generated by tumor measurement between passage 3–5 (F3-5). Media of tumor volume was showed.

Mentions: Thirty-one patient NSCLC specimens were harvested and implanted subcutaneously into SCID mice. Ten patient-derived NSCLC xenograft models from the thirty-one implantations were established in consecutive passages in nude mice (Table 1). NSCLC patient clinical information is also listed in Table 1. None of the patients received any therapies prior to surgery. The original patient NSCLC tissues were implanted into SCID mice subcutaneously and then growing xenograft tissues were implanted into nude mice starting from the second generation of models. The model success rate was 45% (14/31) in the first generation of SCID mice, and then 32% (10/31) in the second and subsequent generations. After the second generation, patient-derived NSCLC xenograft models became stable without further changes in model survival and tumor take-on rates. All ten established patient-derived NSCLC xenograft models showed kinetic growth curves in passage 3 (Figure 1). Examination of autopsies in NSCLC-bearing mice from these xenograft mouse models at 2 ~ 3 months post-implantation revealed no evidence of metastases in brain, lung, liver or kidney. The xenograft tissues were analyzed by H&E staining for pathology assessment. The patient-derived NSCLC xenograft tissues exhibited similar morphology to that of the patient tissues from which the primary models were derived (data not shown). Following this, established patient NSCLC xenografts were submitted for model characterization and further validation by targeted therapy.


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)

In vivo growth curves of patient-derived NSCLC xenograft models. Tumor growth curves of patient-derived NSCLC xenograft models. The models were established subcutaneously and tumor growth curves in passable and stable xenograft models were generated by tumor measurement between passage 3–5 (F3-5). Media of tumor volume was showed.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: In vivo growth curves of patient-derived NSCLC xenograft models. Tumor growth curves of patient-derived NSCLC xenograft models. The models were established subcutaneously and tumor growth curves in passable and stable xenograft models were generated by tumor measurement between passage 3–5 (F3-5). Media of tumor volume was showed.
Mentions: Thirty-one patient NSCLC specimens were harvested and implanted subcutaneously into SCID mice. Ten patient-derived NSCLC xenograft models from the thirty-one implantations were established in consecutive passages in nude mice (Table 1). NSCLC patient clinical information is also listed in Table 1. None of the patients received any therapies prior to surgery. The original patient NSCLC tissues were implanted into SCID mice subcutaneously and then growing xenograft tissues were implanted into nude mice starting from the second generation of models. The model success rate was 45% (14/31) in the first generation of SCID mice, and then 32% (10/31) in the second and subsequent generations. After the second generation, patient-derived NSCLC xenograft models became stable without further changes in model survival and tumor take-on rates. All ten established patient-derived NSCLC xenograft models showed kinetic growth curves in passage 3 (Figure 1). Examination of autopsies in NSCLC-bearing mice from these xenograft mouse models at 2 ~ 3 months post-implantation revealed no evidence of metastases in brain, lung, liver or kidney. The xenograft tissues were analyzed by H&E staining for pathology assessment. The patient-derived NSCLC xenograft tissues exhibited similar morphology to that of the patient tissues from which the primary models were derived (data not shown). Following this, established patient NSCLC xenografts were submitted for model characterization and further validation by targeted therapy.

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