Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534).
Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534).
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DOI：
10.1371/journal.pone.0076551
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Khan J
中科院分区：
文献类型：
--
作者：
Li SQ;Cheuk AT;Shern JF;Song YK;Hurd L;Liao H;Wei JS;Khan J
横纹肌肉瘤是儿童最常见的软组织肉瘤。尽管现代治疗取得了进展，但复发或转移性疾病患者的临床预后非常差。成纤维细胞生长因子受体4（FGFR 4）是一种细胞表面酪氨酸激酶受体，其参与正常的肌发生和肌肉再生，但通常在分化的肌肉组织中不表达。已经报道了FGFR 4的扩增和突变激活在RMS中并促进肿瘤进展。因此，FGFR 4是RMS患者的一个易处理的治疗靶点。在这项研究中，我们使用嵌合Ba/F3 TEL-FGFR 4构建体来测试五种酪氨酸激酶抑制剂，据报道，这些抑制剂在纳摩尔范围内特异性抑制FGFR。我们发现泊那替尼（AP 24534）是最有效的FGFR 4抑制剂，IC 50在纳摩尔范围内。Ponatinib通过增加细胞凋亡抑制表达野生型或突变型FGFR 4的RMS细胞的生长。野生型和突变型FGFR 4及其下游靶点STAT 3的磷酸化也被泊那替尼抑制。最后，泊那替尼治疗抑制了表达突变FGFR 4的RMS小鼠模型中的肿瘤生长。因此，我们的数据表明，泊那替尼是一种潜在有效的治疗剂，用于治疗由FGFR 4信号通路失调驱动的RMS肿瘤。
Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Despite advances in modern therapy, patients with relapsed or metastatic disease have a very poor clinical prognosis. Fibroblast Growth Factor Receptor 4 (FGFR4) is a cell surface tyrosine kinase receptor that is involved in normal myogenesis and muscle regeneration, but not commonly expressed in differentiated muscle tissues. Amplification and mutational activation of FGFR4 has been reported in RMS and promotes tumor progression. Therefore, FGFR4 is a tractable therapeutic target for patients with RMS. In this study, we used a chimeric Ba/F3 TEL-FGFR4 construct to test five tyrosine kinase inhibitors reported to specifically inhibit FGFRs in the nanomolar range. We found ponatinib (AP24534) to be the most potent FGFR4 inhibitor with an IC50 in the nanomolar range. Ponatinib inhibited the growth of RMS cells expressing wild-type or mutated FGFR4 through increased apoptosis. Phosphorylation of wild-type and mutated FGFR4 as well as its downstream target STAT3 was also suppressed by ponatinib. Finally, ponatinib treatment inhibited tumor growth in a RMS mouse model expressing mutated FGFR4. Therefore, our data suggests that ponatinib is a potentially effective therapeutic agent for RMS tumors that are driven by a dysregulated FGFR4 signaling pathway.
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影响因子：
6.2
作者：
Ognjanovic, Simona;Linabery, Amy M.;Charbonneau, Bridget;Ross, Julie A.
通讯作者：
Ross, Julie A.
影响因子：
5.7
作者：
Gozgit JM;Wong MJ;Wardwell S;Tyner JW;Loriaux MM;Mohemmad QK;Narasimhan NI;Shakespeare WC;Wang F;Druker BJ;Clackson T;Rivera VM
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Rivera VM
影响因子：
11.2
作者：
Davicioni, Elai;Finckenstein, Friedrich Graf;Anderson, Michael J.
通讯作者：
Anderson, Michael J.
DOI：
10.1158/1078-0432.ccr-11-2056
发表时间：
2012-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Shukla N;Ameur N;Yilmaz I;Nafa K;Lau CY;Marchetti A;Borsu L;Barr FG;Ladanyi M
通讯作者：
Ladanyi M
DOI：
10.2741/klint
发表时间：
1999-02-15
期刊：
Frontiers in Bioscience
影响因子：
--
作者：
Klint, Peter;Claesson-Welsh, Lena
通讯作者：
Claesson-Welsh, Lena