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

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), f...

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Bibliographic Details
Published in:Cancer science 2019-10, Vol.110 (10), p.3215-3224
Main Authors: Kita, Kenji, Fukuda, Koji, Takahashi, Hiro, Tanimoto, Azusa, Nishiyama, Akihiro, Arai, Sachiko, Takeuchi, Shinji, Yamashita, Kaname, Ohtsubo, Koshiro, Otani, Sakiko, Yanagimura, Naohiro, Suzuki, Chiaki, Ikeda, Hiroko, Tamura, Masaya, Matsumoto, Isao, Yano, Seiji
Format: Article
Language:English
Subjects:
Adenocarcinoma
Adenocarcinoma of Lung - drug therapy
Adenocarcinoma of Lung - genetics
Adenocarcinoma of Lung - pathology
Aged
Aged, 80 and over
Animals
Antibodies
Cancer therapies
Carcinoma, Large Cell - drug therapy
Carcinoma, Large Cell - genetics
Carcinoma, Large Cell - pathology
Carcinoma, Non-Small-Cell Lung - drug therapy
Carcinoma, Non-Small-Cell Lung - genetics
Carcinoma, Non-Small-Cell Lung - pathology
Carcinoma, Squamous Cell - drug therapy
Carcinoma, Squamous Cell - genetics
Carcinoma, Squamous Cell - pathology
Cell culture
Cell Line, Tumor
Cell Proliferation - drug effects
Clonal deletion
Deoxyribonucleic acid
DNA
Drug Resistance, Neoplasm - drug effects
Drug Screening Assays, Antitumor
Drugs
EGFR mutation
EGFR‐TKI
Epidermal growth factor
Epidermal growth factor receptors
ErbB Receptors - antagonists & inhibitors
ErbB Receptors - genetics
Experiments
Female
Gefitinib
Gene deletion
Gene expression
Genomes
Grants
Hairless
Humans
Kinases
Lung cancer
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Lung Neoplasms - pathology
Lymph nodes
Male
Medical research
Mesenchyme
Metastases
Mice
Mice, Hairless
Mice, SCID
Middle Aged
mRNA
Mutation
Non-small cell lung carcinoma
non‐small cell lung cancer
Original
Patients
patient‐derived xenograft
Positron emission tomography
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Protein-tyrosine kinase
Sensitivity analysis
SHO mouse
Small cell lung carcinoma
Squamous cell carcinoma
Tumor Microenvironment - drug effects
Tumors
Xenograft Model Antitumor Assays
Xenografts
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Summary: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‐PrkdcscidHrhr). 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 18F‐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. We successfully established 10 PDX. 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 EGFR mutations (L858R or exon 19 deletion) and were sensitive to EGFR tyrosine kinase inhibitors. Furthermore, in one of the two PDX with an EGFR mutation, osimertinib resistance was induced. 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.
ISSN:1347-9032
1349-7006
DOI:10.1111/cas.14171