Inhibitory effects of the mitogen-activated protein kinase kinase inhibitor CI-1040 on the proliferation and tumor growth of thyroid cancer cells with BRAF or RAS mutations
Inhibitory effects of the mitogen-activated protein kinase kinase inhibitor CI-1040 on the proliferation and tumor growth of thyroid cancer cells with BRAF or RAS mutations
复制标题
DOI：
10.1210/jc.2007-0097
复制
发表时间：
2007-12-01
影响因子：
5.8
通讯作者：
Xing, Mingzhao
中科院分区：
文献类型：
--
作者：
Liu, Dingxie;Liu, Zhi;Xing, Mingzhao
内容：靶向MAPK通路中的MAPK激酶（MEK）是甲状腺癌潜在有效的治疗策略。目的：本研究的目的是研究MEK抑制剂CI-1040对甲状腺癌的基因型依赖性治疗潜力。实验设计：我们检测了CI-1040对增殖、凋亡、转化、甲状腺基因再表达、结果：CI- 1040对携带BRAF或RAS突变的细胞增殖有明显抑制作用，但对携带RET/PTC重排或野生型等位基因的细胞增殖无明显抑制作用。例如，携带BRAF突变的KAT 10细胞和DRO细胞以及携带H-RAS突变的C643细胞的IC 50值分别为0.365、0.031和0.429 μ M，而携带RET/PTC 1的TPC 1细胞以及野生型MRO和WRO细胞的IC 50值分别为44、46和278 μ M。CI-1040在DRO细胞中观察到促凋亡作用，在其他细胞中观察到细胞抑制作用。CI-1040可诱导部分BRAF突变携带细胞中细胞周期蛋白D1的下调和部分甲状腺基因的重新表达，并抑制所有细胞的转化。CI-1040也抑制裸鼠移植瘤的生长来自KAT 10或C643细胞，但不是来自MRO cells.Conclusions：我们第一次证明了有效的抑制作用的MEK抑制剂，CI-1040，对甲状腺癌细胞，其中一些，特别是细胞增殖和肿瘤生长，似乎是BRAF突变或RAS突变的选择性。我们的数据鼓励在甲状腺癌患者中进行CI-1040的临床试验。
Context: Targeting MAPK kinase (MEK) in the MAPK pathway is a potentially effective therapeutic strategy for thyroid cancer.Objective: The objective of the study was to investigate genotype-dependent therapeutic potential of the MEK inhibitor CI-1040 for thyroid cancer.Experimental Design: We examined the effects of CI-1040 on proliferation, apoptosis, transformation, thyroid gene reexpression, and xenograft tumor growth with respect to genotypes in 10 thyroid tumor cell lines.Results: Cell proliferation was potently inhibited by CI- 1040 in cells harboring BRAF or RAS mutations but not in cells harboring RET/PTC rearrangement or wild-type alleles. For example, the IC50 values for BRAF mutation-harboring KAT10 cells and DRO cells and H-RAS mutation-harboring C643 cells were 0.365, 0.031, and 0.429 mu M, respectively, whereas the IC50 values for RET/PTC1-harboring TPC1 cells and the wild-type MRO and WRO cells were 44, 46, and 278 mu M, respectively. Proapoptotic effect of CI-1040 was seen in DRO cells, and cytostatic effect was seen in other cells. Down-regulation of cyclin D1 and reexpression of some thyroid genes were induced by CI-1040 in some BRAF mutation-harboring cells, and transformation was inhibited in all cells. CI-1040 also inhibited the growth of xenograft tumors in nude mice derived from KAT10 or C643 cells but not that derived from MRO cells.Conclusions: We for the first time demonstrated potent inhibitory effects of a MEK inhibitor, CI-1040, on thyroid cancer cells, some of which, particularly cell proliferation and tumor growth, seemed to be BRAF mutation or RAS mutation selective. Our data encourage a clinical trial on CI-1040 in thyroid cancer patients.