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Cancer Sci. 2019 Oct;110(10):3215-3224. doi: 10.1111/cas.14171.

Patient-derived xenograft models of non-small cell lung cancer for evaluating targeted drug sensitivity and resistance.

Author information

1
Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
2
Central Research Resource Branch, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
3
Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
4
Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
5
Division of Pathology, Kanazawa University Hospital, Kanazawa, Japan.
6
Department of Thoracic, Cardiovascular and General Surgery, Kanazawa University, Kanazawa, Japan.

Abstract

Patient-derived xenograft (PDX) models are a useful tool in cancer biology research. However, the number of lung cancer PDX is limited. In the present study, we successfully established 10 PDX, including three adenocarcinoma (AD), six squamous cell carcinoma (SQ) and one large cell carcinoma (LA), from 30 patients with non-small cell lung cancer (NSCLC) (18 AD, 10 SQ, and 2 LA), mainly in SCID hairless outbred (SHO) mice (Crlj:SHO-Prkdcscid Hrhr ). Histology of SQ, advanced clinical stage (III-IV), status of lymph node metastasis (N2-3), and maximum standardized uptake value ≥10 when evaluated using a delayed 18 F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scan was associated with successful PDX establishment. Histological analyses showed that PDX had histology similar to that of patients' surgically resected tumors (SRT), whereas components of the microenvironment were replaced with murine cells after several passages. Next-generation sequencing analyses showed that after two to six passages, PDX preserved the majority of the somatic mutations and mRNA expressions of the corresponding SRT. Two out of three PDX with AD histology had epidermal growth factor receptor (EGFR) mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and osimertinib. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced that was associated with epithelial-to-mesenchymal transition. This study presented 10 serially transplantable PDX of NSCLC in SHO mice and showed the use of PDX with an EGFR mutation for analyses of EGFR-TKI resistance.

KEYWORDS:

EGFR mutation; EGFR-TKI; SHO mouse; non-small cell lung cancer; patient-derived xenograft

PMID:
31432603
PMCID:
PMC6778641
DOI:
10.1111/cas.14171
[Indexed for MEDLINE]
Free PMC Article

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