Reversal of c-MET-mediated Resistance to Cytotoxic Anticancer Drugs by a Novel c-MET Inhibitor TAS-115.
Reversal of c-MET-mediated Resistance to Cytotoxic Anticancer Drugs by a Novel c-MET Inhibitor TAS-115.
复制标题
新型 c-MET 抑制剂 TAS-115 逆转 c-MET 介导的细胞毒性抗癌药物耐药性。
作者：
E. Kunii;H. Ozasa;T. Oguri;K. Maeno;S. Fukuda;T. Uemura;O. Takakuwa;H. Ohkubo;M. Takemura;A. Niimi
背景
细胞N-甲基-N '-亚硝基胍人骨肉瘤转化基因（c-MET）蛋白是肝细胞生长因子的受体酪氨酸激酶。我们最近发现，c-MET蛋白的表达和激活在大多数具有细胞毒性抗癌药物抗性的小细胞肺癌细胞系中增强，并且下调c-MET降低了对这些药物的抗性。
材料和方法
在三种非小细胞肺癌（NSCLC）细胞系中研究了c-MET的表达，包括六种对细胞毒性抗癌药物具有抗性的细胞株。为了评估c-MET活化对耐药性的影响，我们研究了在存在新型c-MET抑制剂TAS-115的情况下的药物敏感性。
结果
在某些细胞毒性抗癌药物耐药NSCLC细胞系中，c-MET表达和活化也增强，TAS-115抑制c-MET活化可降低这些细胞系对抗癌药物的耐药性。
结论
通过肝细胞生长因子/c-MET信号激活的细胞抗癌药物耐药机制不限于小细胞肺癌细胞系，TAS-115可能能够逆转这些癌细胞的耐药性。
BACKGROUND
The cellular N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene (c-MET) protein is the receptor tyrosine kinase for hepatocyte growth factor. We recently found that c-MET protein expression and activation were enhanced in the majority of small cell lung cancer cell lines with cytotoxic anticancer drug resistance, and that down-regulation of c-MET reduced resistance to these drugs.
MATERIALS AND METHODS
Expression of c-MET was studied in three non-small cell lung cancer (NSCLC) cell lines, including six resistant cell strains to cytotoxic anticancer drugs. To assess the effect of c-MET activation on drug resistance, we studied drug sensitivity in the presence of a novel c-MET inhibitor TAS-115.
RESULTS
c-MET expression and activation are also enhanced in some cytotoxic anticancer drug-resistant NSCLC cell lines, and inhibition of c-MET activation by TAS-115 reduced resistance of these cell lines to anticancer drugs.
CONCLUSION
The mechanism of cellular resistance to anticancer drugs via hepatocyte growth factor/c-MET signal activation is not restricted to small cell lung cancer cell lines, and TAS-115 might be able to reverse the drug resistance of these cancer cells.