Corresponding Authors: Yan Zhou, Department of Pathology, School of Basic Medical Sciences, Peking (Beijing) University, Beijing, China.
Mol Cancer Ther. 2014 Jan;13(1):134-43. doi: 10.1158/1535-7163.MCT-13-0187. Epub 2013 Oct 29.
Aberrantly activated c-MET signaling occurs in several cancers, promoting the development of c-MET inhibitors. In this study, we found that eight of eight thyroid cancer cell lines (including six anaplastic thyroid cell lines) have prominent expression of c-MET protein. Fifty percent of the thyroid cancer cell lines (four of eight) were growth inhibited by two small molecule c-MET inhibitors (tivantinib and crizotinib) associated with apoptosis and G(2)-M cell-cycle arrest. However, crizotinib did not inhibit 50% proliferation of thyroid cancer cells (SW1736 and TL3) at a concentration at which the drug completely inhibited ligand-stimulated c-MET phosphorylation. However, tivantinib was less potent than crizotinib at inhibiting c-MET phosphorylation, but was more potent than crizotinib at decreasing cell growth. Suppressing c-MET protein expression and phosphorylation using siRNA targeting c-MET did not induce cell-cycle arrest and apoptosis. Taken together, tivantinib and crizotinib have off-target(s) activity, contributing to their antitumor activity. In vivo study showed that crizotinib markedly inhibited the growth of thyroid cancer cells (SW1736) in immunodeficient mice. In summary, c-MET inhibitors (tivantinib and crizotinib) suppress the growth of aggressive thyroid cancer cells, and this potential therapeutic benefit results from their non-MET-targeting effects.
异常激活的 c-MET 信号发生在几种癌症中，促进了 c-MET 抑制剂的发展。在这项研究中，我们发现 8 种甲状腺癌细胞系（包括 6 种间变性甲状腺癌细胞系）中 c-MET 蛋白表达明显。两种小分子 c-MET 抑制剂（tivantinib 和 crizotinib）与细胞凋亡和 G2-M 细胞周期阻滞相关，可抑制 50%的甲状腺癌细胞系（8 种中的 4 种）的生长。然而，crizotinib 并不能在抑制配体刺激的 c-MET 磷酸化的药物浓度下抑制 50%的甲状腺癌细胞（SW1736 和 TL3）的增殖。然而，tivantinib 抑制 c-MET 磷酸化的效力不如 crizotinib，但降低细胞生长的效力比 crizotinib更强。使用靶向 c-MET 的 siRNA 抑制 c-MET 蛋白表达和磷酸化并没有诱导细胞周期阻滞和细胞凋亡。总之，tivantinib 和 crizotinib 具有非靶点（s）活性，这有助于它们的抗肿瘤活性。体内研究表明，crizotinib 显著抑制了免疫缺陷小鼠甲状腺癌细胞（SW1736）的生长。综上所述，c-MET 抑制剂（tivantinib 和 crizotinib）抑制侵袭性甲状腺癌细胞的生长，这种潜在的治疗益处源自于它们的非 MET 靶向作用。
