Acquired resistance to BRAF inhibition induces epithelial-to-mesenchymal transition in BRAF (V600E) mutant thyroid cancer by c-Met-mediated AKT activation.
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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DOI：
10.18632/oncotarget.13480
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发表时间：
2017-01-03
期刊：
影响因子：
--
通讯作者：
Koh YW
中科院分区：
文献类型：
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作者：
Byeon HK;Na HJ;Yang YJ;Ko S;Yoon SO;Ku M;Yang J;Kim JW;Ban MJ;Kim JH;Kim DH;Kim JM;Choi EC;Kim CH;Yoon JH;Koh YW
此前，作者已经发现，在 BRAF (V600E) 突变型未变性甲状腺癌中，c-Met 在 BRAF 抑制剂治疗后介导 PI3K/AKT 通路的重新激活，从而导致获得性耐药。因此，BRAF和c-Met的双重抑制导致持续的治疗反应，从而最大化靶向治疗的特异性抗肿瘤效果。本研究更进一步，旨在研究BRAF抑制剂获得性耐药对BRAF突变型甲状腺癌细胞上皮间质转化（EMT）的影响以及联合治疗的双重抑制作用。选择两种甲状腺癌细胞系8505C和BCPAP，并用BRAF抑制剂PLX4032处理，并检查和比较其对EMT的影响。在原位异种移植小鼠模型中进行了进一步的研究。与 BCPAP 细胞不同，BRAF 抑制剂耐药的 8505C 细胞表现出 EMT 相关标记物（如波形蛋白、β-连环蛋白和 CD44）表达增加。 PLX4032 和 c-Met 抑制剂 PHA665752 的联合治疗可逆转 EMT。体内也证实了类似的结果。 c-Met介导的PI3K/AKT通路的重新激活有助于BRAF（V600E）突变型未变性甲状腺癌细胞对PLX4032的耐药性，并通过上调EMT机制进一步促进肿瘤细胞迁移和侵袭。 BRAF 和 c-Met 的双重抑制导致 EMT 逆转，表明治疗反应最大。
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.