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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)1678-1687
Number of pages10
JournalMolecular Carcinogenesis
Volume55
Issue number11
DOIs
Publication statusPublished - 2016 Nov 1

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Phosphatidylinositol 3-Kinases
Thyroid Neoplasms
Heterografts
Cell Line
Mutation
Drug Resistance
PLX4032
Melanoma
Signal Transduction
Therapeutics
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Cite this

Byeon, Hyung Kwon ; Na, Hwi Jung ; Yang, Yeon Ju ; Kwon, Hyeong Ju ; Chang, Jae Won ; Ban, Myung Jin ; Kim, Won Shik ; Shin, Dong Yeob ; Lee, Eun Jig ; Koh, Yoon Woo ; Yoon, Joo Heon ; Choi, Eun Chang. / c-Met-mediated reactivation of PI3K/AKT signaling contributes to insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition. In: Molecular Carcinogenesis. 2016 ; Vol. 55, No. 11. pp. 1678-1687.
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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.",
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c-Met-mediated reactivation of PI3K/AKT signaling contributes to insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition. / Byeon, Hyung Kwon; Na, Hwi Jung; Yang, Yeon Ju; Kwon, Hyeong Ju; Chang, Jae Won; Ban, Myung Jin; Kim, Won Shik; Shin, Dong Yeob; Lee, Eun Jig; Koh, Yoon Woo; Yoon, Joo Heon; Choi, Eun Chang.

In: Molecular Carcinogenesis, Vol. 55, No. 11, 01.11.2016, p. 1678-1687.

Research output: Contribution to journalArticle

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T1 - c-Met-mediated reactivation of PI3K/AKT signaling contributes to insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition

AU - Byeon, Hyung Kwon

AU - Na, Hwi Jung

AU - Yang, Yeon Ju

AU - Kwon, Hyeong Ju

AU - Chang, Jae Won

AU - Ban, Myung Jin

AU - Kim, Won Shik

AU - Shin, Dong Yeob

AU - Lee, Eun Jig

AU - Koh, Yoon Woo

AU - Yoon, Joo Heon

AU - Choi, Eun Chang

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