Frequent activation of EGFR in advanced chordomas.
Frequent activation of EGFR in advanced chordomas.
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DOI：
10.1186/2045-3329-1-4
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发表时间：
2011-07-25
影响因子：
--
通讯作者：
Sciot R
中科院分区：
文献类型：
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作者：
Dewaele B;Maggiani F;Floris G;Ampe M;Vanspauwen V;Wozniak A;Debiec-Rychter M;Sciot R
脊索瘤是一种罕见的肿瘤，起源于中线骨骼轴的脊索残余，目前的治疗仅限于手术和放射治疗。最近的报道表明，受体酪氨酸激酶（RTK）可能是必不可少的生存或增殖的脉络膜细胞，提供了RTK靶向治疗的理论基础。然而，报告的数据是相互矛盾的，最有可能是由于用于研究的各种肿瘤标本和异质性的方法。在本研究中，我们使用广泛的检测方法对这种罕见的实体进行了全面的表征，以寻找相关的治疗靶点。采用PDGFRB、CSF 1 R和EGFR探针，通过免疫组织化学和荧光原位杂交（FISH）对42例脉络膜标本（21例原发性和21例晚期）的组织学特征进行了评估。其中22例病例的冷冻材料可用（9例原发性和13例晚期肿瘤），选择性地使用全基因组4.3 K TK-CGH阵列、磷酸激酶抗体阵列或Western免疫印迹进行分析。该研究通过KIT、PDGFRB、CSF 1 R和EGFR的直接测序进行补充。我们证明EGFR是脊索瘤中最常见和最显著的RTK激活。此外，与EGFR激活同时，肿瘤通常显示替代RTK的共激活。AKT的一致激活、肿瘤抑制基因PTEN等位基因的频繁丢失、上游RTK和下游效应物如p70 S6 K和mTOR的反复激活都表明PI 3 K/AKT途径是脊索瘤转化的重要介导物。鉴于脊索瘤中信号传导的复杂性，靶向多个RTK和下游效应物的联合治疗方案可能在这些肿瘤中最有效。根据特定肿瘤的分子特征，精心选择患者进行个性化治疗是值得期待的。
Chordomas are rare neoplasms, arising from notochordal remnants in the midline skeletal axis, for which the current treatment is limited to surgery and radiotherapy. Recent reports suggest that receptor tyrosine kinases (RTK) might be essential for the survival or proliferation of chordoma cells, providing a rationale for RTK targeted therapy. Nevertheless, the reported data are conflicting, most likely due to the assorted tumor specimens used for the studies and the heterogeneous methodological approaches. In the present study, we performed a comprehensive characterization of this rare entity using a wide range of assays in search for relevant therapeutic targets. Histopathological features of 42 chordoma specimens, 21 primary and 21 advanced, were assessed by immunohistochemistry and fluorescent in situ hybridization (FISH) using PDGFRB, CSF1R, and EGFR probes. Twenty-two of these cases, for which frozen material was available (nine primary and 13 advanced tumors), were selectively analyzed using the whole-genome 4.3 K TK-CGH-array, phospho-kinase antibody array or Western immunoblotting. The study was supplemented by direct sequencing of KIT, PDGFRB, CSF1R and EGFR. We demonstrated that EGFR is frequently and the most significantly activated RTK in chordomas. Furthermore, concurrent to EGFR activation, the tumors commonly reveal co-activation of alternative RTK. The consistent activation of AKT, the frequent loss of the tumor suppressor PTEN allele, the recurrent activation of upstream RTK and of downstream effectors like p70S6K and mTOR, all indicate the PI3K/AKT pathway as an important mediator of transformation in chordomas. Given the complexity of the signaling in chordomas, combined treatment regimens targeting multiple RTK and downstream effectors are likely to be the most effective in these tumors. Personalized therapy with careful selection of the patients, based on the molecular profile of the specific tumor, is anticipated.