ABT-869 inhibits the proliferation of Ewing Sarcoma cells and suppresses platelet-derived growth factor receptor beta and c-KIT signaling pathways.
ABT-869 inhibits the proliferation of Ewing Sarcoma cells and suppresses platelet-derived growth factor receptor beta and c-KIT signaling pathways.
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DOI：
10.1158/1535-7163.mct-09-0812
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发表时间：
2010-03
影响因子：
5.7
通讯作者：
Sakamoto KM
中科院分区：
文献类型：
--
作者：
Ikeda AK;Judelson DR;Federman N;Glaser KB;Landaw EM;Denny CT;Sakamoto KM
Ewing肉瘤（EWS）家族肿瘤是儿童和青少年中最常见的肿瘤之一，其特征是EWS基因易位。尽管化疗取得了进展，但转移性EWS的预后很差，5年后的总生存率不到30%。EWS肿瘤细胞表达酪氨酸激酶受体、血小板衍生生长因子受体（PDGFR）和c-KIT。ABT-869是一种多靶点小分子抑制剂，靶向fms样酪氨酸激酶-3 （FLT-3）、c-KIT、血管内皮生长受体（VEGFR）和pdgfr。为了确定ABT-869对EWS细胞的潜在治疗效果，我们研究了ABT-869对EWS细胞系和异种移植小鼠模型的影响。ABT-869对2株EWS细胞株A4573和TC71的增殖抑制作用，作用72 h后IC50分别为1.25 μM和2 μM。PDGFRβ、c-KIT和ERKs的磷酸化也被抑制。为了检验ABT-869在体内的作用，我们给小鼠注射了EWS细胞。我们在异种移植小鼠模型中观察到EWS肿瘤细胞的生长受到抑制，并在转移性EWS小鼠模型中观察到生存时间延长。因此，我们的体外和体内研究表明，ABT-869通过抑制PDGFRβ和c-KIT途径抑制EWS细胞的增殖。
Ewing Sarcoma (EWS) family of tumors is one of the most common tumors diagnosed in children and adolescents and is characterized by a translocation involving the EWS gene. Despite advances in chemotherapy, the prognosis of metastatic EWS is poor with an overall survival of less than 30% after 5 years. EWS tumor cells express the receptor tyrosine kinases, platelet-derived growth factor receptor (PDGFR) and c-KIT. ABT-869 is a multi-targeted small molecule inhibitor that targets Fms-like tyrosine kinase-3 (FLT-3), c-KIT, vascular endothelial growth receptors (VEGFR) and PDGFRs. To determine the potential therapeutic benefit of ABT-869 in EWS cells, we examined the effects of ABT-869 on EWS cell lines and xenograft mouse models. ABT-869 inhibited the proliferation of two EWS cell lines, A4573 and TC71, at an IC50 of 1.25 μM and 2 μM after 72 hours of treatment, respectively. Phosphorylation of PDGFRβ, c-KIT, and ERKs was also inhibited. To examine the effects of ABT-869 in vivo, the drug was given to mice injected with EWS cells. We observed inhibition of growth of EWS tumor cells in a xenograft mouse model and prolonged survival in a metastatic mouse model of EWS. Therefore, our in vitro and in vivo studies demonstrate that ABT-869 inhibits proliferation of EWS cells through inhibition of PDGFRβ and c-KIT pathways.