Acquired resistance to BRAF inhibition induces epithelial-tomesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation

Hyung Kwon Byeon, Hwi Jung Na, Yeon Ju Yang, Sooah Ko, SunOch Yoon, Minhee Ku, Jaemoon Yang, Jae Wook Kim, Myung Jin Ban, Ji Hoon Kim, Da Hee Kim, Jung Min Kim, Eun Chang Choi, Chang-Hoon Kim, Joo Heon Yoon, Yoonwoo Koh

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Previously, the authors have identified that c-Met mediates reactivation of the PI3K/AKT pathway following BRAF inhibitor treatment in BRAF (V600E) mutant anaplastic thyroid cancer, thereby contributing to the acquired drug resistance. Therefore dual inhibition of BRAF and c-Met led to sustained treatment response, thereby maximizing the specific anti-tumor effect of targeted therapy. The present study goes one step further and aims to investigate the effect of acquired resistance of BRAF inhibitor on epithelial-to-mesenchymal transition (EMT) in BRAF mutant thyroid cancer cells and the effect of dual inhibition from combinatorial therapy. Two thyroid cancer cell lines, 8505C and BCPAP were selected and treated with BRAF inhibitor, PLX4032 and its effect on EMT were examined and compared. Further investigation was carried out in orthotopic xenograft mouse models. Unlike BCPAP cells, the BRAF inhibitor resistant 8505C cells showed increased expressions of EMT related markers such as vimentin, β-catenin, and CD44. The combinatorial treatment of PLX4032 and PHA665752, a c-Met inhibitor reversed EMT. Similar results were confirmed in vivo. c-Met-mediated reactivation of the PI3K/AKT pathway contributes to the drug resistance to PLX4032 in BRAF (V600E) mutant anaplastic thyroid cancer cells and further promotes tumor cell migration and invasion by upregulated EMT mechanism. Dual inhibition of BRAF and c-Met leads to reversal of EMT, suggesting a maximal therapeutic response.

Original languageEnglish
Pages (from-to)596-609
Number of pages14
JournalOncotarget
Volume8
Issue number1
DOIs
Publication statusPublished - 2017 Jan 1

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Epithelial-Mesenchymal Transition
Thyroid Neoplasms
Phosphatidylinositol 3-Kinases
Drug Resistance
Catenins
Vimentin
Heterografts
Cell Movement
Neoplasms
Therapeutics
Cell Line
PLX4032

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Byeon, Hyung Kwon ; Na, Hwi Jung ; Yang, Yeon Ju ; Ko, Sooah ; Yoon, SunOch ; Ku, Minhee ; Yang, Jaemoon ; Kim, Jae Wook ; Ban, Myung Jin ; Kim, Ji Hoon ; Kim, Da Hee ; Kim, Jung Min ; Choi, Eun Chang ; Kim, Chang-Hoon ; Yoon, Joo Heon ; Koh, Yoonwoo. / Acquired resistance to BRAF inhibition induces epithelial-tomesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation. In: Oncotarget. 2017 ; Vol. 8, No. 1. pp. 596-609.
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title = "Acquired resistance to BRAF inhibition induces epithelial-tomesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation",
abstract = "Previously, the authors have identified that c-Met mediates reactivation of the PI3K/AKT pathway following BRAF inhibitor treatment in BRAF (V600E) mutant anaplastic thyroid cancer, thereby contributing to the acquired drug resistance. Therefore dual inhibition of BRAF and c-Met led to sustained treatment response, thereby maximizing the specific anti-tumor effect of targeted therapy. The present study goes one step further and aims to investigate the effect of acquired resistance of BRAF inhibitor on epithelial-to-mesenchymal transition (EMT) in BRAF mutant thyroid cancer cells and the effect of dual inhibition from combinatorial therapy. Two thyroid cancer cell lines, 8505C and BCPAP were selected and treated with BRAF inhibitor, PLX4032 and its effect on EMT were examined and compared. Further investigation was carried out in orthotopic xenograft mouse models. Unlike BCPAP cells, the BRAF inhibitor resistant 8505C cells showed increased expressions of EMT related markers such as vimentin, β-catenin, and CD44. The combinatorial treatment of PLX4032 and PHA665752, a c-Met inhibitor reversed EMT. Similar results were confirmed in vivo. c-Met-mediated reactivation of the PI3K/AKT pathway contributes to the drug resistance to PLX4032 in BRAF (V600E) mutant anaplastic thyroid cancer cells and further promotes tumor cell migration and invasion by upregulated EMT mechanism. Dual inhibition of BRAF and c-Met leads to reversal of EMT, suggesting a maximal therapeutic response.",
author = "Byeon, {Hyung Kwon} and Na, {Hwi Jung} and Yang, {Yeon Ju} and Sooah Ko and SunOch Yoon and Minhee Ku and Jaemoon Yang and Kim, {Jae Wook} and Ban, {Myung Jin} and Kim, {Ji Hoon} and Kim, {Da Hee} and Kim, {Jung Min} and Choi, {Eun Chang} and Chang-Hoon Kim and Yoon, {Joo Heon} and Yoonwoo Koh",
year = "2017",
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Byeon, HK, Na, HJ, Yang, YJ, Ko, S, Yoon, S, Ku, M, Yang, J, Kim, JW, Ban, MJ, Kim, JH, Kim, DH, Kim, JM, Choi, EC, Kim, C-H, Yoon, JH & Koh, Y 2017, 'Acquired resistance to BRAF inhibition induces epithelial-tomesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation', Oncotarget, vol. 8, no. 1, pp. 596-609. https://doi.org/10.18632/oncotarget.13480

Acquired resistance to BRAF inhibition induces epithelial-tomesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation. / Byeon, Hyung Kwon; Na, Hwi Jung; Yang, Yeon Ju; Ko, Sooah; Yoon, SunOch; Ku, Minhee; Yang, Jaemoon; Kim, Jae Wook; Ban, Myung Jin; Kim, Ji Hoon; Kim, Da Hee; Kim, Jung Min; Choi, Eun Chang; Kim, Chang-Hoon; Yoon, Joo Heon; Koh, Yoonwoo.

In: Oncotarget, Vol. 8, No. 1, 01.01.2017, p. 596-609.

Research output: Contribution to journalArticle

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T1 - Acquired resistance to BRAF inhibition induces epithelial-tomesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation

AU - Byeon, Hyung Kwon

AU - Na, Hwi Jung

AU - Yang, Yeon Ju

AU - Ko, Sooah

AU - Yoon, SunOch

AU - Ku, Minhee

AU - Yang, Jaemoon

AU - Kim, Jae Wook

AU - Ban, Myung Jin

AU - Kim, Ji Hoon

AU - Kim, Da Hee

AU - Kim, Jung Min

AU - Choi, Eun Chang

AU - Kim, Chang-Hoon

AU - Yoon, Joo Heon

AU - Koh, Yoonwoo

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Previously, the authors have identified that c-Met mediates reactivation of the PI3K/AKT pathway following BRAF inhibitor treatment in BRAF (V600E) mutant anaplastic thyroid cancer, thereby contributing to the acquired drug resistance. Therefore dual inhibition of BRAF and c-Met led to sustained treatment response, thereby maximizing the specific anti-tumor effect of targeted therapy. The present study goes one step further and aims to investigate the effect of acquired resistance of BRAF inhibitor on epithelial-to-mesenchymal transition (EMT) in BRAF mutant thyroid cancer cells and the effect of dual inhibition from combinatorial therapy. Two thyroid cancer cell lines, 8505C and BCPAP were selected and treated with BRAF inhibitor, PLX4032 and its effect on EMT were examined and compared. Further investigation was carried out in orthotopic xenograft mouse models. Unlike BCPAP cells, the BRAF inhibitor resistant 8505C cells showed increased expressions of EMT related markers such as vimentin, β-catenin, and CD44. The combinatorial treatment of PLX4032 and PHA665752, a c-Met inhibitor reversed EMT. Similar results were confirmed in vivo. c-Met-mediated reactivation of the PI3K/AKT pathway contributes to the drug resistance to PLX4032 in BRAF (V600E) mutant anaplastic thyroid cancer cells and further promotes tumor cell migration and invasion by upregulated EMT mechanism. Dual inhibition of BRAF and c-Met leads to reversal of EMT, suggesting a maximal therapeutic response.

AB - Previously, the authors have identified that c-Met mediates reactivation of the PI3K/AKT pathway following BRAF inhibitor treatment in BRAF (V600E) mutant anaplastic thyroid cancer, thereby contributing to the acquired drug resistance. Therefore dual inhibition of BRAF and c-Met led to sustained treatment response, thereby maximizing the specific anti-tumor effect of targeted therapy. The present study goes one step further and aims to investigate the effect of acquired resistance of BRAF inhibitor on epithelial-to-mesenchymal transition (EMT) in BRAF mutant thyroid cancer cells and the effect of dual inhibition from combinatorial therapy. Two thyroid cancer cell lines, 8505C and BCPAP were selected and treated with BRAF inhibitor, PLX4032 and its effect on EMT were examined and compared. Further investigation was carried out in orthotopic xenograft mouse models. Unlike BCPAP cells, the BRAF inhibitor resistant 8505C cells showed increased expressions of EMT related markers such as vimentin, β-catenin, and CD44. The combinatorial treatment of PLX4032 and PHA665752, a c-Met inhibitor reversed EMT. Similar results were confirmed in vivo. c-Met-mediated reactivation of the PI3K/AKT pathway contributes to the drug resistance to PLX4032 in BRAF (V600E) mutant anaplastic thyroid cancer cells and further promotes tumor cell migration and invasion by upregulated EMT mechanism. Dual inhibition of BRAF and c-Met leads to reversal of EMT, suggesting a maximal therapeutic response.

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