Research Papers:
Acquired resistance to BRAF inhibition induces epithelial-to-mesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation
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Abstract
Hyung Kwon Byeon1, Hwi Jung Na1, Yeon Ju Yang1, Sooah Ko1, Sun Och Yoon2, Minhee Ku3,4, Jaemoon Yang3,5, Jae Wook Kim6, Myung Jin Ban6, Ji-Hoon Kim7, Da Hee Kim1, Jung Min Kim1, Eun Chang Choi1, Chang-Hoon Kim1,8, Joo-Heon Yoon1,8,9, Yoon Woo Koh1,8
1Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Republic of Korea
2Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
3Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea
4Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea
5YUHS-KRIBB Medical Convergence Research Institute, Seoul, Republic of Korea
6Department of Otorhinolaryngology, Soonchunhyang University College of Medicine, Republic of Korea
7Department of Otorhinolaryngology-Head and Neck Surgery, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
8The Airway Mucus Institute, Yonsei University College of Medicine, Seoul, Republic of Korea
9Research Center for Human Natural Defense System, Yonsei University College of Medicine, Seoul, Republic of Korea
Correspondence to:
Yoon Woo Koh, email: [email protected]
Keywords: thyroid cancer, molecular targeted therapy, drug resistance, BRAF mutation, epithelial-mesenchymal transition
Received: September 23, 2016 Accepted: November 12, 2016 Published: November 21, 2016
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.
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