Department of General Surgery, Jiaxing Maternity and Child Health Care Hospital, No. 2468 Central East Road, Nanhu District, Jiaxing 314000, Zhejiang, China.
Department of Oncology Surgery, the First Hospital of Jiaxing, No. 1882 Zhonghuan South Road, Jiaxing 314000, Zhejiang, China.
Biochem Cell Biol. 2020 Jun;98(3):443-448. doi: 10.1139/bcb-2019-0354. Epub 2020 May 25.
Medullary thyroid cancer (MTC) is the third most common thyroid cancer. (Rearranged in Transformation) gene mutations are considered as one of the major drivers of MTC. Vandetanib suppresses RET activity, and has shown promise in clinical trials. Unfortunately, acquired resistance to vandetanib has been observed in MTC, although the mechanism was largely unknown. We investigated the critical role of YAP (Yes-Associated Protein) on vandetanib resistance in MTC. For this, TT cells (medullary thyroid cancer cells) were treated with vandetanib for 3 months to generate a vandetanib-resistant cell line (TT-R). We investigated the role of YAP on vandetanib-resistance in TT-R cells by performing cell proliferation and colony formation assays, and examined the antitumor effects of YAP inhibitor and vandetanib in a mouse model of xenografted MTC. The TT-R cells displayed 6-fold higher IC to vandetanib than the TT cells. Overexpression of YAP resulted in resistance to vandetanib, whereas knockdown of re-sensitized the TT-R cells to vandetanib. The YAP inhibitor synergized with vandetanib on tumor inhibition. Our results suggest that YAP plays an important role in acquired resistance to vandetanib in MTC, providing basis for combating MTC with YAP inhibitor and vandetanib.
甲状腺髓样癌（MTC）是第三大常见的甲状腺癌。（重排转化）基因突变为 MTC 的主要驱动因素之一。凡德他尼抑制 RET 活性，在临床试验中显示出良好的疗效。不幸的是，MTC 中已经观察到对凡德他尼的获得性耐药，尽管其机制在很大程度上尚不清楚。我们研究了 YAP（Yes-Associated Protein）在 MTC 对凡德他尼耐药中的关键作用。为此，用凡德他尼处理 TT 细胞（甲状腺髓样癌细胞）3 个月以生成凡德他尼耐药细胞系（TT-R）。我们通过细胞增殖和集落形成实验研究了 YAP 在 TT-R 细胞中对凡德他尼耐药的作用，并在 MTC 异种移植小鼠模型中研究了 YAP 抑制剂和凡德他尼的抗肿瘤作用。TT-R 细胞对凡德他尼的 IC 比 TT 细胞高 6 倍。YAP 的过表达导致对凡德他尼的耐药性，而 YAP 的敲低则使 TT-R 细胞对凡德他尼重新敏感。YAP 抑制剂与凡德他尼联合使用可抑制肿瘤生长。我们的研究结果表明，YAP 在 MTC 对凡德他尼的获得性耐药中起重要作用，为使用 YAP 抑制剂和凡德他尼对抗 MTC 提供了依据。
