Her-2/neu-triggered intracellular tyrosine kinase activation: in vivo relevance of ligand-independent activation mechanisms and impact upon the efficacy of trastuzumab-based treatment.
Her-2/neu-triggered intracellular tyrosine kinase activation: in vivo relevance of ligand-independent activation mechanisms and impact upon the efficacy of trastuzumab-based treatment.
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DOI：
10.1038/sj.bjc.6601160
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发表时间：
2003-09-15
影响因子：
8.8
通讯作者：
Singer CF
中科院分区：
文献类型：
--
作者：
Hudelist G;Köstler WJ;Attems J;Czerwenka K;Müller R;Manavi M;Steger GG;Kubista E;Zielinski CC;Singer CF
Her-2/neu细胞外结构域（ECD）的蛋白水解切割已显示在体外启动代表Her-2/neu活化的受体磷酸化。本研究旨在评价ECD切割对Her-2/neu激活的临床相关性，以及在接受抗Her-2/neu抗体曲妥珠单抗治疗的患者中通过酪氨酸激酶磷酸化反映的活性细胞内Her-2/neu信号传导的后果。使用酶联免疫吸附试验评估了62例接受基于曲妥珠单抗治疗的Her-2/neu过表达转移性乳腺癌患者的血清治疗前ECD水平。同时，使用Her-2/neu磷酸化状态特异性抗体（PN 2A）通过免疫组织化学评估肿瘤标本的Her-2/neu活化状态，并与患者的ECD水平和临床病程相关。15例（24%）显示Her-2/neu活化的肿瘤患者的血清ECD水平显著高于未检测到Her-2/neu磷酸化的患者（中位数148.2 vs 28.5 ng ml−1，P=0.010）。而缓解率仅在Her-2/neu磷酸化乳腺癌患者中显示出较高的趋势（47 vs 34%，P=0.197），单因素和多因素分析均显示，Her-2/neu磷酸化乳腺癌患者在曲妥珠单抗治疗下的中位无进展生存期显著延长-11.7（95%CI 5.2-18.3）个月--与缺乏磷酸化Her-2/neu的肿瘤患者中观察到的4.5（95%CI 3.4-5.6）个月的无进展生存期相比（P=0.001）。ECD的蛋白水解裂解代表Her-2/neu体内活化的生物学相关配体非依赖性机制。Her-2/neu激活状态对基于曲妥珠单抗的治疗结局的影响值得在更大规模的前瞻性试验中进一步研究。
Proteolytic cleavage of the Her-2/neu extracellular domain (ECD) has been shown to initiate receptor phosphorylation representing Her-2/neu activation in vitro. The present investigation was performed to evaluate the clinical relevance of ECD cleavage for Her-2/neu activation and the consequences of active intracellular Her-2/neu signalling reflected by tyrosine kinase phosphorylation in patients treated with the anti-Her-2/neu antibody trastuzumab. Sera from 62 patients receiving trastuzumab-based treatment for Her-2/neu overexpressing metastatic breast cancer were assessed for pretreatment ECD levels using an enzyme-linked immunosorbent assay. In parallel, Her-2/neu activation status of tumour specimens was assessed by immunohistochemistry using a Her-2/neu phosphorylation state specific antibody (PN2A) and correlated with the patients’ ECD levels and clinical course of disease. Serum ECD levels were significantly higher in 15 (24%) patients with tumours exhibiting activated Her-2/neu as compared to those without detectable Her-2/neu phosphorylation (median 148.2 vs 28.5 ng ml−1, P=0.010). Whereas response rate only showed a trend to be higher in patients with Her-2/neu-phosphorylated breast cancer (47 vs 34%, P=0.197), both uni- and multivariate analyses revealed that the median progression-free survival under trastuzumab-based treatment was significantly longer in patients with Her-2/neu-phosphorylated breast cancer–11.7 (95% CI 5.2–18.3) months–when compared to the progression-free survival of 4.5 (95% CI 3.4–5.6) months observed in patients with tumours lacking phosphorylated Her-2/neu (P=0.001). Proteolytic cleavage of the ECD represents a biologically relevant ligand-independent mechanism of Her-2/neu activation in vivo. The influence of Her-2/neu activation status upon the outcome of trastuzumab-based therapies merits further investigation in larger prospective trials.
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影响因子：
4.1
作者：
HARDER, KW;OWEN, P;JIRIK, FR
通讯作者：
JIRIK, FR
影响因子：
45.3
作者：
Cobleigh, MA;Vogel, CL;Slamon, DJ
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Slamon, DJ
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45.3
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作者：
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Hynes, NE