Ligand-Independent HER2/HER3/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941
Ligand-Independent HER2/HER3/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941
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DOI：
10.1016/j.ccr.2009.03.020
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发表时间：
2009-05-05
期刊：
影响因子：
50.3
通讯作者：
Sliwkowski, Mark X.
中科院分区：
文献类型：
--
作者：
Junttila, Teemu T.;Akita, Robert W.;Sliwkowski, Mark X.
赫赛汀（曲妥珠单抗）是her2导向乳腺癌治疗的支柱，在辅助治疗和转移性治疗中均使患者受益。在这里，我们描述了曲妥珠单抗的作用机制，即抗体治疗破坏HER2扩增细胞中不依赖配体的HER2/HER3相互作用。解离动力学与HER3去磷酸化和PI3K活性解耦相似，导致近端和远端AKT信号下调，并与曲妥珠单抗的抗增殖作用相关。GDC-0941是一种选择性和有效的PI3K抑制剂，无论是与曲妥珠单抗联合使用，还是治疗曲妥珠单抗耐药细胞和肿瘤，都是非常有效的。
Herceptin (trastuzumab) is the backbone of HER2-directed breast cancer therapy and benefits patients in both the adjuvant and metastatic settings. Here, we describe a mechanism of action for trastuzumab whereby antibody treatment disrupts ligand-independent HER2/HER3 interactions in HER2-amplified cells. The kinetics of dissociation parallels HER3 dephosphorylation and uncoupling from PI3K activity, leading to downregulation of proximal and distal AKT signaling, and correlates with the antiproliferative effects of trastuzumab. A selective and potent PI3K inhibitor, GDC-0941, is highly efficacious both in combination with trastuzumab and in the treatment of trastuzumab-resistant cells and tumors.