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Korean Journal of Head & Neck Oncology 2014;30(2):53-61.
Published online November 30, 2014.
Mechanism of Resistance and Epithelial to Mesenchymal Transition of BRAF(V600E) Mutation Thyroid Anaplastic Cancer to BRAF(V600E) Inhibition Through Feedback Activation of EGFR
Hyung Kwon Byeon;Hwi Jung Na;Yeon Ju Yang;Jae Hong Park;Hyeong Ju Kwon;Jae Won Chang;Myung Jin Ban;Won Shik Kim;Dong Yeob Shin;Eun Jig Lee;Yoon Woo Koh;Eun Chang Choi
BRAF(V600E) 돌연변이 갑상선 역형성암에서 BRAF(V600E) 억제에 의한 EGFR 발현 증가가 표적치료에 대한 저항성발현과 상피-간질세포이행과정에 미치는 영향분석
변형권;나휘정;양연주;박재홍;권형주;장재원;반명진;김원식;신동엽;이은직;고윤우;최은창
Abstract
Background and Objectives:Anaplastic thyroid carcinoma(ATC) is a rare but highly aggressive thyroid ma-lignancy 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 ex-periment 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.
Key Words: BRAF, EGFR, Epithelial-mesenchymal transition, Thyroid anaplastic cancer, BRAF 돌연변이, EGFR
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