Ligand-Independent HER2/HER3/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941

被引：669

作者：

Junttila, Teemu T. ^{[1
]}

Akita, Robert W. ^{[1
]}

Parsons, Kathryn ^{[1
]}

Fields, Carter ^{[1
]}

Phillips, Gail D. Lewis ^{[1
]}

Friedman, Lori S. ^{[1
]}

Sampath, Deepak ^{[1
]}

Sliwkowski, Mark X. ^{[1
]}

机构：

[1] Genentech Inc, Res Oncol, San Francisco, CA 94080 USA

来源：

CANCER CELL | 2009年 / 15卷 / 05期

关键词：

METASTATIC BREAST-CANCER; MONOCLONAL-ANTIBODY; PHOSPHATIDYLINOSITOL; 3-KINASE; TUMOR-CELLS; ERBB2; RECEPTOR; GROWTH; HEREGULIN; KINASE; CHEMOTHERAPY;

D O I：

10.1016/j.ccr.2009.03.020

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：429 / 440

页数：12

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