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 |
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| creator | Junttila, Teemu T. Akita, Robert W. Parsons, Kathryn Fields, Carter Lewis Phillips, Gail D. Friedman, Lori S. Sampath, Deepak Sliwkowski, Mark X. |
| description | 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. |
| doi_str_mv | 10.1016/j.ccr.2009.03.020 |
| format | Article |
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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.</description><subject>Animals</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antibodies, Monoclonal, Humanized</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - metabolism</subject><subject>Cell Line, Tumor</subject><subject>CELLCYCLE</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>Female</subject><subject>Humans</subject><subject>Indazoles - pharmacology</subject><subject>Ligands</subject><subject>Mutation</subject><subject>Phosphatidylinositol 3-Kinases - antagonists & inhibitors</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Receptor, ErbB-2 - antagonists & inhibitors</subject><subject>Receptor, ErbB-2 - metabolism</subject><subject>Receptor, ErbB-3 - antagonists & inhibitors</subject><subject>Receptor, ErbB-3 - metabolism</subject><subject>Signal Transduction - drug effects</subject><subject>SIGNALING</subject><subject>Sulfonamides - pharmacology</subject><subject>Trastuzumab</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhiNERT_gB3BBPnFLdsZO7Kw4oe3SRqzUqipny7Ed6lW-sJOK5cY_x9uNxA0uMyPP876y5k2S9wgZAvLVPtPaZxRgnQHLgMKr5AJLUaaMl_x1nAtWpByhPE8uQ9hD1KBYv0nOcZ0jgsCL5PfOfVe9Save2NHG0k_kdvtAV7Gw1X3FvpLN0I2t_UmqQK5d8PM4WUPqA3n0Kkzzr7lTNYkWx_22aaye3LNtD6Tqn1ztFnZ6suTFbHkdPLm53qQQ__E2OWtUG-y7pV8l375sHze36e7uptp83qU6X-OU2qZUgmuKvMaG5QKLgscOqsgLQJNrQYtcA1DFRG2wNsIIXlLGa8YLoxW7Sj6efEc__JhtmGTngrZtq3o7zEFyQbFkDP4LUih4CYJGEE-g9kMI3jZy9K5T_iAR5DEguZcxIHkMSAKTMaCo-bCYz3VnzV_FkkgEPp0AG2_x7KyXQTvba2ucj7eVZnD_sP8D92ydew</recordid><startdate>20090505</startdate><enddate>20090505</enddate><creator>Junttila, Teemu T.</creator><creator>Akita, Robert W.</creator><creator>Parsons, Kathryn</creator><creator>Fields, Carter</creator><creator>Lewis Phillips, Gail D.</creator><creator>Friedman, Lori S.</creator><creator>Sampath, Deepak</creator><creator>Sliwkowski, Mark X.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20090505</creationdate><title>Ligand-Independent HER2/HER3/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941</title><author>Junttila, Teemu T. ; 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| source | MEDLINE; Cell Press Free Archives; Access via ScienceDirect (Elsevier); EZB-FREE-00999 freely available EZB journals |
| subjects | 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 |
| title | Ligand-Independent HER2/HER3/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941 |
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