A central role for HER3 in HER2-amplified breast cancer:: implications for targeted therapy
A central role for HER3 in HER2-amplified breast cancer:: implications for targeted therapy
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DOI：
10.1158/0008-5472.can-08-0380
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Stern, Howard M.
中科院分区：
文献类型：
--
作者：
Lee-Hoeflich, Si Tuen;Crocker, Lisa;Stern, Howard M.
表皮生长因子受体 (EGFR) 和 HER3 均与 HER2 形成异二聚体，并且独立地被认为是驱动 ILER2 扩增乳腺癌的关键辅助受体。一些研究表明 EGFR 发挥主导作用，鉴于 HER2/EGFR 小分子抑制剂的开发，这一概念重新引起人们的兴趣。其他研究指出 HER3 是主要的辅助受体。为了阐明 EGFR 和 HER3 对 HER2 信号传导的相对贡献，我们通过小干扰 RNA 技术在一组 6 种 HER2 过表达细胞系中研究了受体敲低。有趣的是，在大多数细胞系中，HER3 对于维持细胞增殖与 HER2 一样重要，而 EGFR 则是可有可无的。研究发现，在 HER2 过表达 BT474M1 细胞系中诱导 HER3 敲低可抑制三维培养中的生长，并诱导体内异种移植物的肿瘤快速消退。此外，在 HER2 扩增的乳腺癌组织中观察到 HER3 优先磷酸化，而非 EGFR。鉴于这些数据表明 HER3 作为重要的治疗靶点，我们检查了帕妥珠单抗的活性，帕妥珠单抗是一种 HER2 抗体，通过阻断配体诱导的 HER2/HER3 异二聚化来抑制 HER3 信号传导。帕妥珠单抗在三维培养中抑制配体依赖性形态发生，并在调蛋白依赖性 MDA-MB-175 异种移植模型中诱导肿瘤消退。重要的是，帕妥珠单抗的这些活性与曲妥珠单抗的活性不同，曲妥珠单抗是目前用于治疗 HER2 扩增乳腺癌患者的单克隆抗体。我们的数据表明，在 HER2 扩增的乳腺癌中，抑制 HER3 可能比抑制 EGFR 更具临床相关性，并且还表明，在曲妥珠单抗中添加帕妥珠单抗可能会通过阻断 HER2/HER3 信号传导来增强治疗效果。
Epidermal growth factor receptor (EGFR) and HER3 each form heterodimers with HER2 and have independently been implicated as key coreceptors that drive ILER2-amplified breast cancer. Some studies suggest a dominant role for EGFR, a notion of renewed interest given the development of dual HER2/EGFR small-molecule inhibitors. Other studies point to HER3 as the primary coreceptor. To clarify the relative contributions of EGFR and HER3 to HER2 signaling, we studied receptor knockdown via small interfering RNA technology across a panel of six HER2-overexpressing cell lines. Interestingly, HER3 was as critical as HER2 for maintaining cell proliferation in most cell lines, whereas EGFR was dispensable. Induction of HER3 knockdown in the HER2-overexpressing BT474M1 cell line was found to inhibit growth in three-dimensional culture and induce rapid tumor regression of in vivo xenografts. Furthermore, preferential phosphorylation of HER3, but not EGFR, was observed in HER2-amplified breast cancer tissues. Given these data suggesting HER3 as an important therapeutic target, we examined the activity of pertuzumab, a HER2 antibody that inhibits HER3 signaling by blocking ligand-induced HER2/HER3 heterodimerization. Pertuzumab inhibited ligand-dependent morphogenesis in three-dimensional culture and induced tumor regression in the heregulin-dependent MDA-MB-175 xenograft model. Importantly, these activities of pertuzumab were distinct from those of trastuzumab, a monoclonal antibody currently used for treatment of HER2-amplified breast cancer patients. Our data suggest that inhibition of HER3 may be more clinically relevant than inhibition of EGFR in HER2-amplified breast cancer and also suggest that adding pertuzumab to trastuzumab may augment therapeutic benefit by blocking HER2/HER3 signaling.