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Establishment of a platform of non-small-cell lung cancer patient-derived xenografts with clinical and genomic annotation

Authors
 Han Na Kang  ;  Jae Woo Choi  ;  Hyo Sup Shim  ;  Jinna Kim  ;  Dae Joon Kim  ;  Chang Young Lee  ;  Min Hee Hong  ;  Seong Yong Park  ;  A-Young Park  ;  Eun Joo Shin  ;  Seo Yoon Lee  ;  Kyoung-Ho Pyo  ;  Mi Ran Yun  ;  Hun Mi Choi  ;  Sung Sook Lee  ;  Seok-Young Kim  ;  Hanna Lee  ;  Soonmyung Paik  ;  Byoung Chul Cho  ;  Jin Gu Lee  ;  Hye Ryun Kim 
Citation
 Lung Cancer, Vol.124 : 168-178, 2018 
Journal Title
 Lung Cancer 
ISSN
 0169-5002 
Issue Date
2018
Keywords
Driver mutations ; Non-small-cell lung cancer ; Patient-derived xenograft ; Preclinical model
Abstract
BACKGROUND: Preclinical models that can better predict therapeutic activity in clinical trials are needed in this era of personalized cancer treatment. Herein, we established genomically and clinically annotated patient-derived xenografts (PDXs) from non-small-cell lung cancer (NSCLC) patients and investigated whether these PDXs would faithfully recapitulate patient responses to targeted therapy. METHODS: Patient-derived tumors were implanted in immunodeficient mice and subsequently expanded via re-implantation. Established PDXs were examined by light microscopy, genomic profiling, and in vivo drug testing, and the successful engraft rate was analyzed with the mutation profile, histology, or acquisition method. Finally, the drug responses of PDXs were compared with the clinical responses of the respective patients. RESULTS: Using samples from 122 patients, we established 41 NSCLC PDXs [30 adenocarcinoma (AD), 11 squamous cell carcinoma (SQ)], among which the following driver mutation were observed: 13 EGFR-mutant, 4 ALK-rearrangement, 1 ROS1-rearrangement, 1 PIK3CA-mutant, 1 FGFR1-amplification, and 2 KRAS-mutant. We rigorously characterized the relationship of clinical features to engraftment rate and latency rates. The engraft rates were comparable across histologic type. The AD engraft rate tended to be higher for surgically resected tissues relative to biopsies, whereas similar engraft rates was observed for SQ, irrespective of the acquisition method. Notably, EGFR-mutants demonstrated significantly longer latency time than EGFR-WT (86 vs. 37days, P = 0.007). The clinical responses were recapitulated by PDXs harboring driver gene alteration (EGFR, ALK, ROS1, or FGFR1) which regressed to their target inhibitors, suggesting that established PDXs comprise a clinically relevant platform. CONCLUSION: The establishment of genetically and clinically annotated NSCLC PDXs can yield a robust preclinical tool for biomarker, therapeutic target, and drug discovery.
Full Text
https://linkinghub.elsevier.com/retrieve/pii/S0169-5002(18)30525-7
DOI
10.1016/j.lungcan.2018.08.008
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Dae Joon(김대준)
Kim, Jinna(김진아) ORCID logo https://orcid.org/0000-0002-9978-4356
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Park, Seong Yong(박성용)
Paik, Soon Myung(백순명) ORCID logo https://orcid.org/0000-0001-9688-6480
Shim, Hyo Sup(심효섭) ORCID logo https://orcid.org/0000-0002-5718-3624
Yun, Mi Ran(윤미란)
Lee, Jin Gu(이진구)
Lee, Hanna(이한나)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
Pyo, Kyoung Ho(표경호) ORCID logo https://orcid.org/0000-0001-5428-0288
Hong, Min Hee(홍민희) ORCID logo https://orcid.org/0000-0003-3490-2195
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/163790
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