- Record: found
- Abstract: not found
- Article: not found
Ligand-Independent HER2/HER3/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941
Teemu T. Junttila ,
Robert W. Akita ,
Kathryn Parsons ,
Carter Fields ,
Gail D. Lewis Phillips ,
Lori S. Friedman ,
Deepak Sampath ,
Mark X. Sliwkowski
May 2009
May 2009
Read this article at
There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
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.