Author/Authors :
Junttila، نويسنده , , Teemu T. and Akita، نويسنده , , Robert W. and Parsons، نويسنده , , Kathryn and Fields، نويسنده , , Carter and Lewis Phillips، نويسنده , , Gail D. and Friedman، نويسنده , , Lori S. and Sampath، نويسنده , , Deepak and Sliwkowski، نويسنده , , Mark X.، نويسنده ,
Abstract :
Summary
tin (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.
