Anti-HER3 Domain 1 and 3 Antibodies Reduce Tumor Growth by Hindering HER2/HER3 Dimerization and AKT-Induced MDM2, XIAP, and Fox01 Phosphorylation
Anti-HER3 Domain 1 and 3 Antibodies Reduce Tumor Growth by Hindering HER2/HER3 Dimerization and AKT-Induced MDM2, XIAP, and Fox01 Phosphorylation
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DOI：
10.1593/neo.121960
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发表时间：
2013-03-01
期刊：
影响因子：
4.8
通讯作者：
Chardes, Thierry
中科院分区：
文献类型：
--
作者：
Lazrek, Yassamine;Dubreuil, Olivier;Chardes, Thierry
阻断人表皮生长因子受体 3 (HER3) 和下游磷脂酰肌醇 3-激酶 (PI3K)/AKT 通路是克服耐药性和开发针对目前批准的靶向疗法不合格的癌症的新疗法的先决条件。为此，我们生成了针对 HER3 结构域 1 (D1) 和结构域 3 (D3) 的特异性抗体 (Abs)，这些抗体可识别与神经调节蛋白结合位点不重叠的表位。全人 H4B-121 Ab 和小鼠单克隆 Abs 16D3-C1 和 9F7-F11 抑制异种移植表皮样、胰腺或三阴性乳腺癌细胞的裸鼠肿瘤生长。一种抗 HER3 Ab 与曲妥珠单抗的组合改善了 HER2（低）癌细胞系异种移植小鼠的肿瘤生长抑制，而单独的曲妥珠单抗对此没有显示或中等效果。 Ab 诱导的肿瘤生长破坏与 G(1) 细胞周期停滞、增殖抑制和癌细胞凋亡有关。抗 HER3 Ab 阻断细胞膜上的 HER2/HER3 异二聚化和 HER3 磷酸化，从而抑制下游 AKT 靶点鼠双分钟 2、X 连锁细胞凋亡抑制剂和叉头盒 O1 的磷酸化。这项研究表明，抗 HER3 D1 和 D3 Abs 可能代表胰腺癌和三阴性乳腺癌免疫治疗的新选择。
Blockade of the human epidermal growth factor receptor 3 (HER3) and of the downstream phosphatidylinositide 3-kinase (PI3K)/AKT pathway is a prerequisite for overcoming drug resistance and to develop novel treatments for cancers that are not eligible for the currently approved targeted therapies. To this end, we generated specific antibodies (Abs) against domain 1 (D1) and domain 3 (D3) of HER3 that recognize epitopes that do not overlap with the neuregulin-binding site. The fully human H4B-121 Ab and the mouse monoclonal Abs 16D3-C1 and 9F7-F11 inhibited tumor growth in nude mice xenografted with epidermoid, pancreatic, or triple-negative breast cancer cells. The combination of one anti-HER3 Ab and trastuzumab improved tumor growth inhibition in mice xenografted with HER2(low) cancer cell lines, for which trastuzumab alone shows no or moderate efficiency. Ab-induced disruption of tumor growth was associated with G(1) cell cycle arrest, proliferation inhibition, and apoptosis of cancer cells. Anti-HER3 Abs blocked HER2/HER3 heterodimerization and HER3 phosphorylation at the cell membrane, leading to inhibition of phosphorylation of the downstream AKT targets murine double minute 2, X-linked inhibitor of apoptosis, and forkhead box O1. This study demonstrates that anti-HER3 D1 and D3 Abs could represent a new option for immunotherapy of pancreatic and triple-negative breast cancers.