期刊
JOURNAL OF CLINICAL ONCOLOGY
卷 33, 期 22, 页码 2472-U94出版社
AMER SOC CLINICAL ONCOLOGY
DOI: 10.1200/JCO.2014.60.1492
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资金
- Ontario Research Fund Research Excellence Award [RE-03-020]
- Canadian Cancer Society (CCS) Research Institute [020527, 701595]
- CCS
- Rachelle Archambault Innovation [701637]
- Ontario Premier's Summit Award
- Princess Margaret Cancer Foundation
- Ontario Ministry of Health and Long Term Care
- Terry Fox Foundation
- Ontario Graduate Scholarship
- Graduate Ontario Student Opportunity Trust Fund
- Boehringer-Ingelheim Canada
- Televie (Fonds de la Recherche Scientifique-Fonds National de la Recherche Scientifique, Belgium)
- Terry Fox Foundation Training Program in Molecular Pathology of Cancer at CIHR [STP 53912]
Purpose Although epidermal growth factor receptor (EGFR) -mutated adenocarcinomas initially have high response rates to EGFR tyrosine kinase inhibitors (TKIs), most patients eventually develop resistance. Patient-derived xenografts (PDXs) are considered preferred preclinical models to study the biology of patient tumors. EGFR-mutant PDX models may be valuable tools to study the biology of these tumors and to elucidate mechanisms of resistance to EGFR-targeted therapies. Methods Surgically resected early-stage non-small-cell lung carcinoma (NSCLC) tumors were implanted into nonobese diabetic severe combined immune deficient (NOD-SCID) mice. EGFR TKI treatment was initiated at tumor volumes of 150 L. Gene expression analysis was performed using a microarray platform. Results Of 33 lung adenocarcinomas with EGFR activating mutations, only 6 (18%) engrafted and could be propagated beyond passage one. Engraftment was associated with upregulation of genes involved in mitotic checkpoint and cell proliferation. A differentially expressed gene set between engrafting and nonengrafting patients could identify patients harboring EGFR-mutant tumor with significantly different prognoses in The Cancer Genome Atlas Lung Adenocarcinoma datasets. The PDXs included models with variable sensitivity to first- and second-generation EGFR TKIs and the monoclonal antibody cetuximab. All EGFR-mutant NSCLC PDXs studied closely recapitulated their corresponding patient tumor phenotype and clinical course, including response pattern to EGFR TKIs. Conclusion PDX models closely recapitulate primary tumor biology and clinical outcome. They may serve as important laboratory models to investigate mechanisms of resistance to targeted therapies, and for preclinical testing of novel treatment strategies. (C) 2015 by American Society of Clinical Oncology
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