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C-Met-mediated reactivation of PI3K AKT signaling contributes to insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition

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 BRAF(V600E) 돌연변이 갑상선암에서 BRAF(V600E) 억제에 의한 c-Met 발현 증가가 표적 치료에 대한 저항성 발현에 미치는 영향 분석 
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BRAF (V600E) mutation is the most commonly detected genetic alteration in thyroid cancer. Unlike its high treatment response to selective BRAF inhibitor (PLX4032) in metastatic melanoma, the treatment response in thyroid cancer 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 in order to maximize the effect of targeted therapy. We examined the expression of feedback regulation mechanisms and alterations in the upper signal transduction pathway in thyroid cancer cell lines harboring BRAF mutation. Also we investigated the effect of dual inhibition from combinatorial therapy. Two thyroid cancer cell lines, 8505C (anaplastic thyroid cancer) and BCPAP (papillary thyroid cancer) were selected and treated with PLX4032 and its drug sensitivity 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 orthotopic xenograft mouse models. Unlike BCPAP cells, 8505C cells presented drug resistance to PLX4032 treatment and this was mainly due to increased expression of c-Met. Effective inhibitions of c-Met, p-AKT, and p-ERK were achieved after dual treatment with BRAF inhibitor (PLX4032) and c-Met inhibitor (PHA665752). Similar results were confirmed by in vivo study with orthotopic xenograft mouse model. c-Met-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 c-Met leads to sustained treatment response.
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1. College of Medicine (의과대학) > Others (기타) > 3. Dissertation
Yonsei Authors
Byeon, Hyung Kwon(변형권)
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