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

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 c...

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Veröffentlicht in:	Cancer cell 2009-05, Vol.15 (5), p.429-440
Hauptverfasser:	Junttila, Teemu T., Akita, Robert W., Parsons, Kathryn, Fields, Carter, Lewis Phillips, Gail D., Friedman, Lori S., Sampath, Deepak, Sliwkowski, Mark X.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal, Humanized Antineoplastic Agents - pharmacology Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Cell Line, Tumor CELLCYCLE Drug Resistance, Neoplasm - genetics Female Humans Indazoles - pharmacology Ligands Mutation Phosphatidylinositol 3-Kinases - antagonists & inhibitors Phosphatidylinositol 3-Kinases - genetics Proto-Oncogene Proteins c-akt - metabolism Receptor, ErbB-2 - antagonists & inhibitors Receptor, ErbB-2 - metabolism Receptor, ErbB-3 - antagonists & inhibitors Receptor, ErbB-3 - metabolism Signal Transduction - drug effects SIGNALING Sulfonamides - pharmacology Trastuzumab
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Zusammenfassung:	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.
ISSN:	1535-6108 1878-3686
DOI:	10.1016/j.ccr.2009.03.020