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BRAF(V600E) 돌연변이 갑상선 역형성암에서 BRAF(V600E) 억제에 의한 EGFR 발현 증가가 표적치료에 대한 저항성발현과 상피-간질세포이행과정에 미치는 영향분석

Other Titles
 Mechanism of Resistance and Epithelial to Mesenchymal Transition of BRAF(V600E) Mutation Thyroid Anaplastic Cancer to BRAF(V600E) Inhibition Through Feedback Activation of EGFR 
 변형권  ;  나휘정  ;  양연주  ;  박재홍  ;  권형주  ;  ·장재원  ;  반명진  ;  김원식  ;  신동엽  ;  이은직  ;  고윤우  ;  최은창 
 Korean Journal of Head & Neck Oncology (대한두경부종양학회지), Vol.30(2) : 53-61, 2014 
Journal Title
Korean Journal of Head & Neck Oncology(대한두경부종양학회지)
Issue Date
BRAF ; EGFR ; Epithelial-mesenchymal transition ; Thyroid anaplastic cancer
Background and Objectives : Anaplastic thyroid carcinoma(ATC) is a rare but highly aggressive thyroid malignancy that is associated with an extremely poor survival despite the best multidisciplinary care. BRAF(V600E) mutation is detected in about a quarter of ATC, but unlike its high treatment response to selective BRAF inhibitor (PLX4032) in metastatic melanoma, the treatment response of ATC is reported to be low. The purpose of this study is to investigate the innate resistance mechanism responsible for this low treatment response to BRAF inhibitor and its effect on epithelial-mesenchymal transition(EMT). Materials and Methods : Two ATP cell lines, 8505C and FRO were selected and treated with PLX4032 and its drug sensitivity and effects on cell migration and EMT were examined and compared. Further investigation on the changes in signals responsible for the different treatment response to PLX4032 was carried out and the same experiment was performed on both orthotopic and ectopic xenograft mouse models. Results : FRO cell line was more sensitive to PLX4032 treatment compared to 8505C cell line. The resistance to BRAF inhibition in 8505C was due to increased expression of EGFR. Effective inhibition of both EGFR and p-AKT was achieved after dual treatment with BRAF inhibitor(PLX4032) and EGFR inhibitor(Erlotinib). Similar results were confirmed on in vivo study. Conclusion : EGFR-mediated reactivation of the PI3K/AKT pathway and MAPK pathway contributes to the relative insensitivity of BRAF(V600E) mutant ATC cells to PLX4032. Dual inhibition of BRAF and EGFR leads to sustained treatment response including cell invasiveness.
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1. College of Medicine (의과대학) > Research Institute (부설연구소) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Koh, Yoon Woo(고윤우)
Kim, Won Shik(김원식)
Byeon, Hyung Kwon(변형권)
Shin, Dong Yeob(신동엽) ORCID logo https://orcid.org/0000-0003-1048-7978
Yang, Yeon Ju(양연주)
Lee, Eun Jig(이은직) ORCID logo https://orcid.org/0000-0002-9876-8370
Choi, Eun Chang(최은창)
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