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Co-clinical trials demonstrate predictive biomarkers for dovitinib, an FGFR inhibitor, in lung squamous cell carcinoma

Authors
 H. R. Kim  ;  H. N. Kang  ;  H. S. Shim  ;  E. Y. Kim  ;  J. Kim  ;  D. J. Kim  ;  J. G. Lee  ;  C. Y. Lee  ;  M. H. Hong  ;  S.-M. Kim  ;  H. Kim  ;  K.-H. Pyo  ;  M. R. Yun  ;  H. J. Park  ;  J. Y. Han  ;  H. A. Youn  ;  M.-J. Ahn  ;  S. Paik  ;  T.-M. Kim  ;  B. C. Cho 
Citation
 Annals of Oncology, Vol.28(6) : 1250-1259, 2017 
Journal Title
 Annals of Oncology 
ISSN
 0923-7534 
Issue Date
2017
MeSH
Benzimidazoles/therapeutic use* ; Biomarkers/blood* ; Carcinoma, Squamous Cell/drug therapy* ; Carcinoma, Squamous Cell/genetics ; Clinical Trials as Topic* ; Humans ; Lung Neoplasms/drug therapy* ; Lung Neoplasms/genetics Mutation ; Quinolones/therapeutic use* ; Receptors, Fibroblast Growth Factor/antagonists & inhibitors* ; Receptors, Fibroblast Growth Factor/metabolism ; Signal Transduction ; Whole Exome Sequencing
Keywords
biomarker ; dovitinib ; fibroblast growth factor receptor ; patient-derived xenograft ; squamous cell lung cancer
Abstract
Background: We conducted co-clinical trials in patient-derived xenograft (PDX) models to identify predictive biomarkers for the multikinase inhibitor dovitinib in lung squamous cell carcinoma (LSCC). Methods: The PDX01-02 were established from LSCC patients enrolled in the phase II trial of dovitinib (NCT01861197) and PDX03-05 were established from LSCC patients receiving surgery. These five PDX tumors were subjected to in vivo test of dovitinib efficacy, whole exome sequencing and gene expression profiling. Results: The PDX tumors recapitulate histopathological properties and maintain genomic characteristics of originating tumors. Concordant with clinical outcomes of the trial enrolled-LSCC patients, dovitinib produced substantial tumor regression in PDX-01 and PDX-05, whereas it resulted in tumor progression in PDX-02. PDX-03 and -04 also displayed poor antitumor efficacy to dovitinib. Mutational and genome-wide copy number profiles revealed no correlation between genomic alterations of FGFR1-3 and sensitivity to dovitinib. Of note, gene expression profiles revealed differentially expressed genes including FGF3 and FGF19 between PDX-01 and 05 and PDX-02-04. Pathway analysis identified two FGFR signaling-related gene sets, FGFR ligand binding/activation and SHC-mediated cascade pathway were substantially up-regulated in PDX-01 and 05, compared with PDX-02-04. The comparison of gene expression profiles between dovitinib-sensitive versus -resistant lung cancer cell lines in the Cancer Cell Line Encyclopedia database also found that transcriptional activation of 18 key signaling components in FGFR pathways can predict the sensitivity to dovitinib both in cell lines and PDX tumors. These results highlight FGFR pathway activation as a key molecular determinant for sensitivity to dovitinib. Conclusions: FGFR gene expression signatures are predictors for the response to dovitinib in LSCC.
Full Text
https://academic.oup.com/annonc/article/28/6/1250/3771561
DOI
10.1093/annonc/mdx098
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Eun Young(김은영) ORCID logo https://orcid.org/0000-0002-3281-5744
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
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
Lee, Jin Gu(이진구)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
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/22282913/160283
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