Targeting BRAFV600E with PLX4720 displays potent antimigratory and anti-invasive activity in preclinical models of human thyroid cancer.
Targeting BRAFV600E with PLX4720 displays potent antimigratory and anti-invasive activity in preclinical models of human thyroid cancer.
复制标题
DOI：
10.1634/theoncologist.2010-0317
复制
发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Parangi S
中科院分区：
文献类型：
--
作者：
Nucera C;Nehs MA;Nagarkatti SS;Sadow PM;Mekel M;Fischer AH;Lin PS;Bollag GE;Lawler J;Hodin RA;Parangi S
研究了B-RafV600E突变在侵袭性甲状腺癌中的作用。B-RafV600E可能在甲状腺乳头状癌向间变性甲状腺癌（ATC）发展过程中发挥作用。我们测试了一种高选择性B-RafV600E抑制剂PLX4720对人甲状腺癌细胞系（8505cB-RafV600E、TPC-1RET/PTC-1和野生型B-Raf）和原代人正常甲状腺滤泡细胞（含或不含B-RafV600E）增殖、迁移和侵袭的影响。为了分析bbb900基因突变，采用质谱法进行了大规模基因分型分析。PLX4720对8505c、TPC-1和NT细胞进行了细胞增殖和迁移/侵袭。将8505c或TPC-1细胞原位植入重度联合免疫缺陷小鼠甲状腺。通过定量聚合酶链反应和免疫组织化学进行基因验证。我们发现PLX4720降低了体外细胞增殖和8505c细胞的迁移和侵袭，导致肿瘤进展相关基因的早期下调。plx4720处理过表达B-RafV600E（杂合野生型B-Raf/B-RafV600E）的NT细胞，细胞增殖、迁移和侵袭显著降低。PLX4720处理不能阻断野生型B-Raf对TPC-1细胞的侵袭，在体内肿瘤生长非常低且延迟。在体内，PLX4720治疗8505c原位甲状腺肿瘤可抑制肿瘤侵袭性，并显著上调甲状腺分化标志物甲状腺转录因子1和配对box基因8。在这里，我们已经证明PLX4720优先抑制B-RafV600E甲状腺癌细胞的迁移和侵袭以及肿瘤的侵袭性。正常甲状腺细胞被野生型B-Raf/B-RafV600E产生杂合，模仿大多数人类甲状腺癌的情况。PLX4720在该杂合模型中具有抑制细胞增殖、迁移和侵袭的作用。PLX4720疗法应该被测试并考虑用于治疗B-RafV600E ATC患者的I期研究。
The role of the B-RafV600E mutation in aggressive thyroid cancers is examined. B-RafV600E may play a role in the progression from papillary thyroid cancer to anaplastic thyroid cancer (ATC). We tested the effects of a highly selective B-RafV600E inhibitor, PLX4720, on proliferation, migration, and invasion both in human thyroid cancer cell lines (8505cB-RafV600E and TPC-1RET/PTC-1 and wild-type B-Raf) and in primary human normal thyroid (NT) follicular cells engineered with or without B-RafV600E. Large-scale genotyping analysis by mass spectrometry was performed in order to analyze >900 gene mutations. Cell proliferation and migration/invasion were performed upon PLX4720 treatment in 8505c, TPC-1, and NT cells. Orthotopic implantation of either 8505c or TPC-1 cells into the thyroid of severe combined immunodeficient mice was performed. Gene validations were performed by quantitative polymerase chain reaction and immunohistochemistry. We found that PLX4720 reduced in vitro cell proliferation and migration and invasion of 8505c cells, causing early downregulation of genes involved in tumor progression. PLX4720-treated NT cells overexpressing B-RafV600E (heterozygous wild-type B-Raf/B-RafV600E) showed significantly lower cell proliferation, migration, and invasion. PLX4720 treatment did not block cell invasion in TPC-1 cells with wild-type B-Raf, which showed very low and delayed in vivo tumor growth. In vivo, PLX4720 treatment of 8505c orthotopic thyroid tumors inhibited tumor aggressiveness and significantly upregulated the thyroid differentiation markers thyroid transcription factor 1 and paired box gene 8. Here, we have shown that PLX4720 preferentially inhibits migration and invasion of B-RafV600E thyroid cancer cells and tumor aggressiveness. Normal thyroid cells were generated to be heterozygous for wild-type B-Raf/B-RafV600E, mimicking the condition found in most human thyroid cancers. PLX4720 was effective in reducing cell proliferation, migration, and invasion in this heterozygous model. PLX4720 therapy should be tested and considered for a phase I study for the treatment of patients with B-RafV600E ATC.
登录
查看更多内容
影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
影响因子：
8
作者：
Giordano, TJ;Kuick, R;Nikiforov, YE
通讯作者：
Nikiforov, YE
影响因子：
11.5
作者：
Nucera, Carmelo;Eeckhoute, Jerome;Brown, Myles
通讯作者：
Brown, Myles
影响因子：
11.2
作者：
Nucera, Carmelo;Goldfarb, Melanie;Hodin, Richard;Parangi, Sareh
通讯作者：
Parangi, Sareh
影响因子：
4.8
作者：
Chandrasekaran, S;Guo, NH;Roberts, DD
通讯作者：
Roberts, DD