Clinical utility of patient-derived xenografts to determine biomarkers of prognosis and map resistance pathways in EGFR-mutant lung adenocarcinoma

Erin L. Stewart, Celine Mascaux, Nhu An Pham, Shingo Sakashita, Jenna Sykes, Lucia Kim, Naoki Yanagawa, Ghassan Allo, Kota Ishizawa, Dennis Wang, Chang Qi Zhu, Ming Li, Christine Ng, Ni Liu, Melania Pintilie, Petra Martin, Tom John, Igor Jurisica, Natasha B. Leighl, Benjamin G. NeelThomas K. Waddell, Frances A. Shepherd, Geoffrey Liu, Ming Sound Tsao

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)

Abstract

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 μL. 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.

Original languageEnglish
Pages (from-to)2472-2480
Number of pages9
JournalJournal of Clinical Oncology
Volume33
Issue number22
DOIs
Publication statusPublished - 2015 Aug 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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