Clinical Utility of Patient Derived Xenografts to Determine Biomarkers of Prognosis and Map Resistance Pathways in EGFR-Mutant Lung Adenocarcinoma

ABSTRACT: PURPOSE: Although epidermal growth factor receptor (EGFR) mutated adenocarcinomas initially have very high response rates to EGFR tyrosine kinase inhibitors (TKIs), most atients 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 non-obese diabetic severe combined immune deficient (NODSCID) mice. EGFR TKI treatment was initiated at tumor volumes of 150 mm3. Gene expression analysis was performed using microarray platform. RESULTS: Of 33 lung adenocarcinomas with EGFR activating mutations, only 6 engrafted 18%) 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 non-engrafting patients could identify EGFRmutant patients with significantly different prognoses in The Cancer Genome Atlas (TCGA) 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. CONCLUSIONS: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE63685 | GEO | 2017/03/28

SECONDARY ACCESSION(S): PRJNA268686

REPOSITORIES: GEO