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Antitumor Activity and Acquired Resistance Mechanism of Dovitinib (TKI258) in RET-Rearranged Lung Adenocarcinoma

Authors
 Chan Woo Kang  ;  Kang Won Jang  ;  Jinyoung Sohn  ;  Sung-Moo Kim  ;  Kyoung-Ho Pyo  ;  Hwan Kim  ;  Mi Ran Yun  ;  Han Na Kang  ;  Hye Ryun Kim  ;  Sun Min Lim  ;  Yong Wha Moon  ;  Soonmyung Paik  ;  Dae Joon Kim  ;  Joo Hang Kim  ;  Byoung Chul Cho 
Citation
 MOLECULAR CANCER THERAPEUTICS, Vol.14(10) : 2238-2248, 2015 
Journal Title
 MOLECULAR CANCER THERAPEUTICS 
ISSN
 1535-7163 
Issue Date
2015
MeSH
Adenocarcinoma/drug therapy* ; Adenocarcinoma/enzymology ; Adenocarcinoma/pathology ; Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology* ; Apoptosis ; Benzimidazoles/chemistry ; Benzimidazoles/pharmacology* ; Catalytic Domain ; Cell Cycle Checkpoints ; Cell Line, Tumor ; Drug Resistance, Neoplasm* ; Enzyme Activation ; HEK293 Cells ; Humans ; Inhibitory Concentration 50 ; Lung Neoplasms/drug therapy* ; Lung Neoplasms/enzymology ; Lung Neoplasms/pathology ; Mice, Nude ; Models, Molecular ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-ret/antagonists & inhibitors* ; Proto-Oncogene Proteins c-ret/chemistry ; Quinolones/chemistry ; Quinolones/pharmacology* ; Tumor Burden/drug effects ; Xenograft Model Antitumor Assays ; src-Family Kinases/metabolism
Abstract
RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore antitumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell-cycle arrest at G0-G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong antitumor effect of dovitinib was observed in an LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene-set enrichment analysis of gene expression and phosphor-kinase revealed that Src, a central gene in focal adhesion, was activated in LC-2/ad DR cells. Saracatinib, an src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src.
Files in This Item:
T201505000.pdf Download
DOI
10.1158/1535-7163.MCT-15-0350
Appears in Collections:
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Thoracic and Cardiovascular Surgery (흉부외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kang, Chan Woo(강찬우)
Kang, Han Na(강한나)
Kim, Dae Joon(김대준)
Kim, Joo Hang(김주항)
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Kim, Hwan(김환)
Moon, Yong Wha(문용화)
Paik, Soon Myung(백순명) ORCID logo https://orcid.org/0000-0001-9688-6480
Yun, Mi Ran(윤미란)
Lim, Sun Min(임선민)
Jang, Kang Won(장강원)
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
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/156983
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