title: c-Met-mediated reactivation of PI3K/AKT signaling contributes to insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition.
abstract: 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. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyung Kwon
authors.initials: HK
authors.lastname: Byeon
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hwi Jung
authors.initials: HJ
authors.lastname: Na
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Yeon Ju
authors.initials: YJ
authors.lastname: Yang
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyeong Ju
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Department of Otorhinolaryngology, Chungnam National University College of Medicine, Daejeon, Republic of Korea.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Chang
authors.affiliation: Department of Otorhinolaryngology, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea.
authors.forename: Myung Jin
authors.initials: MJ
authors.lastname: Ban
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Won Shik
authors.initials: WS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Dong Yeob
authors.initials: DY
authors.lastname: Shin
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Jig
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea. ywkohent@yuhs.ac.
authors.forename: Yoon Woo
authors.initials: YW
authors.lastname: Koh
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea.|The Airway Mucus Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.|Research Center for Human Natural Defense System, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Joo-Heon
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Chang
authors.initials: EC
authors.lastname: Choi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D013450:Sulfones / Q000008:administration & dosage* / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one; D007211:Indoles; D013449:Sulfonamides; D013450:Sulfones; D000077484:Vemurafenib; D019869:Phosphatidylinositol 3-Kinases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt
keywords: drug resistance; molecular targeted therapy; mutation; thyroid neoplasm/drug therapy