The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma.
The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma.
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DOI：
10.18632/oncotarget.2648
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发表时间：
2014-12-30
期刊：
影响因子：
--
通讯作者：
Versleijen-Jonkers YM
中科院分区：
文献类型：
--
作者：
Fleuren ED;Hillebrandt-Roeffen MH;Flucke UE;Te Loo DM;Boerman OC;van der Graaf WT;Versleijen-Jonkers YM
尤文肉瘤(ES)患者迫切需要新的靶点。因此，我们研究了致癌受体酪氨酸激酶(RTK)AXL在ES中的表达和遗传异常，并确定了AXL靶向对细胞存活和迁移的效果。首先，用RT-PCR方法检测29例ES组织中Ax1和Gas6(配体)基因的表达。Axl低、中、高表达分别占31%(n=9)、48%(n=14)和21%(n=6)。Gas6在所有标本中都大量存在。接下来，我们用免疫组织化学方法检测了25例ES患者的36个肿瘤(原发、化疗后、转移和复发)中Ax1蛋白的表达。17%(n=6)、19%(n=7)和36%(n=13)的标本中低、中、高表达Axl蛋白。在原发肿瘤(n=15)中，Axl高表达与低表达患者(61个月vs.194个月，p=0.026)相比，总体生存期显著降低。AXL RTK区未检测到遗传异常(n=29)。AXL抑制剂BGB324影响所有受试ES细胞系(n=5~6)的存活率(IC500.79~2.13Mol/L)和体外迁移能力(n=5~6)。BGB324使化疗耐药的ES-4细胞对长春新碱和阿霉素增敏。这些数据表明Axl是一种潜在的新颖的、可用于ES的治疗靶点。
New targets for Ewing sarcoma (ES) patients are urgently needed. Therefore, we investigated the expression and genetic aberrations of the oncogenic receptor tyrosine kinase (RTK) AXL in ES and determined the efficacy of AXL targeting on cell viability and migration. First, AXL and Gas6 (ligand) mRNA expression was determined by RT-PCR on 29 ES samples. Low, medium and high AXL mRNA expression was observed in 31% (n = 9), 48% (n = 14) and 21% (n = 6) of samples. Gas6 was abundantly present in all specimens. We next tested AXL protein expression immunohistochemically in 36 tumors (primary, post-chemotherapy, metastasized and relapsed samples) from 25 ES patients. Low, medium and high AXL protein expression was observed in 17% (n = 6), 19% (n = 7) and 36% (n = 13) of samples. In primary tumors (n = 15), high AXL expression correlated significantly with a worse overall survival compared to patients with lower expression (61 vs. 194 months, p = 0.026). No genetic aberrations were detected in the AXL RTK domain (n = 29). The AXL-inhibitor BGB324 affected viability (IC50 0.79–2.13 μmol/L) and migratory potential of all tested ES cell lines in vitro (n = 5–6). BGB324 chemosensitized chemotherapy-resistant ES-4 cells to vincristine and doxorubicin. These data suggest that AXL is a potential novel, druggable therapeutic target in ES.
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影响因子：
6.2
作者：
DuBois, Steven G.;Marina, Neyssa;Glade-Bender, Julia
通讯作者：
Glade-Bender, Julia
DOI：
10.1158/1078-0432.ccr-11-1488
发表时间：
2011-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Fleuren ED;Versleijen-Jonkers YM;van de Luijtgaarden AC;Molkenboer-Kuenen JD;Heskamp S;Roeffen MH;van Laarhoven HW;Houghton PJ;Oyen WJ;Boerman OC;van der Graaf WT
通讯作者：
van der Graaf WT
影响因子：
20.3
作者：
Ben-Batalla, Isabel;Schultze, Alexander;Loges, Sonja
通讯作者：
Loges, Sonja
影响因子：
20.3
作者：
Ghosh, Asish K.;Secreto, Charla;Kay, Neil E.
通讯作者：
Kay, Neil E.
影响因子：
11.2
作者：
Avilla, Elvira;Guarino, Valentina;Melillo, Rosa Marina
通讯作者：
Melillo, Rosa Marina