Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers.
Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers.
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DOI：
10.1158/0008-5472.can-10-1872
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发表时间：
2011-03-01
期刊：
影响因子：
11.2
通讯作者：
Arteaga CL
中科院分区：
文献类型：
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作者：
Ghosh R;Narasanna A;Wang SE;Liu S;Chakrabarty A;Balko JM;González-Angulo AM;Mills GB;Penuel E;Winslow J;Sperinde J;Dua R;Pidaparthi S;Mukherjee A;Leitzel K;Kostler WJ;Lipton A;Bates M;Arteaga CL
在HER2基因扩增的乳腺癌细胞中，HER2受体以单体、同二聚体和异二聚体的形式存在于细胞表面，与EGFR/HER3结合。治疗HER2+乳腺癌的治疗性抗体曲妥珠单抗不能阻断配体诱导的HER2异二聚体，这表明它不能有效地抑制HER2信号转导。因此，在HER2驱动的肿瘤中，HER2寡聚体状态可能预测曲妥珠单抗临床反应的几率。为了验证这一假设，我们产生了稳定表达嵌合HER2-FKBP分子的未转化的人乳腺上皮细胞，该嵌合分子可以通过添加FKBP配体AP1510有条件地诱导同源二聚，或者通过添加异二聚体配体EGF/转化生长因子α或HER3诱导与EGFR或HER3异源二聚。AP1510、EGF和hereglin分别诱导表达HER2-FKBP的MCF10A细胞生长。正如预期的那样，曲妥珠单抗抑制同源二聚体介导的细胞生长，但不抑制异二聚体介导的细胞生长。相反，阻断HER2异二聚化的HER2抗体pertuzumab抑制了Hereguline诱导的生长，但不抑制AP1510。最后，HER2/EGFR酪氨酸激酶抑制剂拉帕替尼阻断了同源和异源二聚体诱导的生长。曲妥珠单抗抑制AP1510诱导的ERK1/2磷酸化和Shc-HER2同源二聚体结合，但不抑制转化生长因子α诱导的AKT磷酸化。与这些观察一致的是，在一组HER2过度表达的患者中，HER2同源二聚体水平高与曲妥珠单抗治疗后较长的进展时间相关。总之，我们的发现证实了HER2寡聚体状态调节HER2信号的假设，也认为曲妥珠单抗对同源二聚体的敏感性反映了无法激活PI3K/AKT途径。我们的结果最重要的临床意义之一是，高水平的HER2同源二聚体可能预测曲妥珠单抗的阳性反应。
In breast cancer cells with HER2 gene amplification, HER2 receptors exist on the cell surface as monomers, homodimers and heterodimers with EGFR/HER3. The therapeutic antibody trastuzumab, an approved therapy for HER2+ breast cancer, cannot block ligand-induced HER2 heterodimers, suggesting it cannot effectively inhibit HER2 signaling. Hence, HER2 oligomeric states may predict the odds of a clinical response to trastuzumab in HER2-driven tumors. To test this hypothesis, we generated non-transformed human MCF10A mammary epithelial cells stably expressing a chimeric HER2-FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510, or instead induced to heterodimerize with EGFR or HER3 by adding the heterodimer ligands EGF/TGFα or heregulin. AP1510, EGF, and heregulin each induced growth of MCF10A cells expressing HER2-FKBP. As expected, trastuzumab inhibited homodimer-mediated but not heterodimer-mediated cell growth. In contrast, the HER2 antibody pertuzumab, which blocks HER2 heterodimerization, inhibited growth induced by heregulin but not AP1510. Lastly, HER2/EGFR tyrosine kinase inhibitor lapatinib blocked both homodimer- and heterodimer-induced growth. AP1510 triggered phosphorylation of Erk1/2 but not AKT, whereas trastuzumab inhibited AP1510-induced Erk1/2 phosphorylation and Shc-HER2 homodimer binding, but not TGFα-induced AKT phosphorylation. Consistent with these observations, high levels of HER2 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of HER2-overexpressing patients. Together, our findings corroborate the hypothesis that HER2 oligomeric states regulate HER2 signaling, also arguing that trastuzumab sensitivity of homodimers reflects an inability to activate the PI3K/AKT pathway. One of the most important clinical implications of our results is that high levels of HER2 homodimers may predict a positive response to trastuzumab.