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

 Hyung Kwon Byeon  ;  Hwi Jung Na  ;  Yeon Ju Yang  ;  Hyeong Ju Kwon  ;  Jae Won Chang  ;  Myung Jin Ban  ;  Won Shik Kim  ;  Dong Yeob Shin  ;  Eun Jig Lee  ;  Yoon Woo Koh  ;  Joo-Heon Yoon  ;  Eun Chang Choi 
 Molecular Carcinogenesis, Vol.55(11) : 1678-1687, 2016 
Journal Title
 Molecular Carcinogenesis 
Issue Date
Animals ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Drug Synergism ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Indoles/administration & dosage* ; Indoles/pharmacology ; Mice ; Mutation ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins B-raf/genetics* ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-met/metabolism* ; Signal Transduction/drug effects ; Sulfonamides/administration & dosage* ; Sulfonamides/pharmacology ; Sulfones/administration & dosage* ; Sulfones/pharmacology ; Thyroid Neoplasms/drug therapy ; Thyroid Neoplasms/genetics* ; Thyroid Neoplasms/metabolism ; Up-Regulation* ; Xenograft Model Antitumor Assays
drug resistance ; molecular targeted therapy ; mutation ; thyroid neoplasm/drug therapy
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 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 anaplastic thyroid cancer cells to PLX4032. Dual inhibition of BRAF and c-Met leads to sustained treatment response.
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1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
고윤우(Kho, Yoon Woo)
김원식(Kim, Won Shik)
변형권(Byeon, Hyung Kwon)
신동엽(Shin, Dong Yeob) ORCID logo https://orcid.org/0000-0003-1048-7978
윤주헌(Yoon, Joo Heon)
이은직(Lee, Eun Jig) ORCID logo https://orcid.org/0000-0002-9876-8370
최은창(Choi, Eun Chang)
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