Small molecule inhibitor regorafenib inhibits RET signaling in neuroblastoma cells and effectively suppresses tumor growth in vivo.
Small molecule inhibitor regorafenib inhibits RET signaling in neuroblastoma cells and effectively suppresses tumor growth in vivo.
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DOI：
10.18632/oncotarget.22011
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发表时间：
2017-11-28
期刊：
影响因子：
--
通讯作者：
Yang J
中科院分区：
文献类型：
--
作者：
Chen Z;Zhao Y;Yu Y;Pang JC;Woodfield SE;Tao L;Guan S;Zhang H;Bieerkehazhi S;Shi Y;Patel R;Vasudevan SA;Yi JS;Muscal JA;Xu GT;Yang J
神经母细胞瘤（NB）是最常见的儿童颅外实体瘤，在儿童中继续引起显著的癌症相关发病率和死亡率。致癌受体酪氨酸激酶（RTKs）的失调已被证明有助于各种人类癌症的肿瘤发生，靶向这些RTKs具有治疗益处。RET是在NB中普遍表达的RTK， RET的高表达与NB患者预后不良相关。本文中，我们报道了NB细胞增殖需要RET，并且小分子抑制剂regorafenib （BAY 73-4506）阻断胶质细胞源性神经营养因子（GDNF）诱导的NB细胞RET信号传导，并在体外和体内抑制NB生长。我们发现瑞非尼显著抑制NB细胞的增殖和集落形成能力。此外，regorafenib在原位异种NB小鼠模型和TH-MYCN转基因NB小鼠模型中均抑制肿瘤生长。最后，瑞非尼显著提高TH-MYCN转基因荷瘤小鼠的总生存率。总之，我们的研究表明，RET是NB的潜在治疗靶点，应该研究使用一种新的RET抑制剂，如瑞非尼，作为NB患儿的治疗选择。
Neuroblastoma (NB), the most common extracranial pediatric solid tumor, continues to cause significant cancer-related morbidity and mortality in children. Dysregulation of oncogenic receptor tyrosine kinases (RTKs) has been shown to contribute to tumorigenesis in various human cancers and targeting these RTKs has had therapeutic benefit. RET is an RTK which is commonly expressed in NB, and high expression of RET correlates with poor outcomes in patients with NB. Herein we report that RET is required for NB cell proliferation and that the small molecule inhibitor regorafenib (BAY 73-4506) blocks glial cell derived neurotrophic factor (GDNF)-induced RET signaling in NB cells and inhibits NB growth both in vitro and in vivo. We found that regorafenib significantly inhibited cell proliferation and colony formation ability of NB cells. Moreover, regorafenib suppressed tumor growth in both an orthotopic xenograft NB mouse model and a TH-MYCN transgenic NB mouse model. Finally, regorafenib markedly improved the overall survival of TH-MYCN transgenic tumor-bearing mice. In summary, our study suggests that RET is a potential therapeutic target in NB, and that using a novel RET inhibitor, like regorafenib, should be investigated as a therapeutic treatment option for children with NB.
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影响因子：
3.7
作者：
Daudigeos-Dubus E;Le Dret L;Lanvers-Kaminsky C;Bawa O;Opolon P;Vievard A;Villa I;Pagès M;Bosq J;Vassal G;Zopf D;Geoerger B
通讯作者：
Geoerger B
影响因子：
4.6
作者：
Chen Z;Wang L;Yao D;Yang T;Cao WM;Dou J;Pang JC;Guan S;Zhang H;Yu Y;Zhao Y;Wang Y;Xu X;Shi Y;Patel R;Zhang H;Vasudevan SA;Liu S;Yang J;Nuchtern JG
通讯作者：
Nuchtern JG
影响因子：
--
作者：
Guan S;Zhao Y;Lu J;Yu Y;Sun W;Mao X;Chen Z;Xu X;Pan J;Sun S;Yang J
通讯作者：
Yang J
影响因子：
--
作者：
Li H;Wang Y;Chen Z;Lu J;Pan J;Yu Y;Zhao Y;Zhang H;Hu T;Liu Q;Yang J
通讯作者：
Yang J
影响因子：
5.7
作者：
Futami, Hitoyasu;Sakai, Ryuichi
通讯作者：
Sakai, Ryuichi