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Mol Carcinog. 2016 Nov;55(11):1678-1687. doi: 10.1002/mc.22418. Epub 2015 Oct 12.

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

Author information

1
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea.
2
Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.
3
Department of Otorhinolaryngology, Chungnam National University College of Medicine, Daejeon, Republic of Korea.
4
Department of Otorhinolaryngology, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea.
5
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
6
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea. ywkohent@yuhs.ac.
7
The Airway Mucus Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
8
Research Center for Human Natural Defense System, Yonsei University College of Medicine, Seoul, Republic of Korea.

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.

KEYWORDS:

drug resistance; molecular targeted therapy; mutation; thyroid neoplasm/drug therapy

PMID:
26456083
DOI:
10.1002/mc.22418
[Indexed for MEDLINE]

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