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Pertuzumab Increases 17-AAG-Induced Degradation of ErbB2, and This Effect Is Further Increased by Combining Pertuzumab with Trastuzumab

Institute of Pathology, Oslo University Hospital, Rikshospitalet University of Oslo, Oslo 0027, Norway
Roche Diagnostics GmbH, Pharma Research Penzberg, Nonnenwald 2, Penzberg 82377, Germany
Department of Pathology, Oslo University Hospital, Rikshospitalet, Post Box 4950 Nydalen, Oslo 0424, Norway
Author to whom correspondence should be addressed.
Pharmaceuticals 2012, 5(7), 674-689;
Received: 20 April 2012 / Revised: 13 June 2012 / Accepted: 21 June 2012 / Published: 28 June 2012
(This article belongs to the Special Issue Hsp90 Inhibitors)
ErbB2 is an important oncogenic protein involved in carcinogenesis of, among others, breast, gastric, and ovarian carcinoma. Over-expression of ErbB2 is found in almost 20% of breast cancers, and this results in proliferative and anti-apoptotic signalling. ErbB2 is therefore an important treatment target. Antibodies recognizing full-length ErbB2 are clinically established, and drugs targeting the ErbB2 stabilizing heat shock protein 90 (Hsp90) are under clinical evaluation. We have investigated effects of the ErbB2-binding antibodies trastuzumab and pertuzumab alone and in combination, as well as the effect of the antibodies in combination with the Hsp90 inhibitor 17-AAG. Our results confirm the notion that combination of different ErbB2-binding antibodies more efficiently down-regulates ErbB2 than does one antibody in isolation. Additionally, our data demonstrate that ErbB2 is most efficiently down-regulated upon incubation with anti-ErbB2 antibodies in combination with Hsp90 inhibitors. The combination of anti-ErbB2 antibodies, and especially the combination of antibodies with 17-AAG, did also increase the inhibition of Akt activation of either agent, which could suggest an anti-proliferative effect. In such case, combining these agents could be beneficial in treatment of tumors not responding to trastuzumab only. View Full-Text
Keywords: 17-AAG; pertuzumab; trastuzumab; Hsp90; ErbB2 17-AAG; pertuzumab; trastuzumab; Hsp90; ErbB2
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Hughes, J.B.; Rødland, M.S.; Hasmann, M.; Madshus, I.H.; Stang, E. Pertuzumab Increases 17-AAG-Induced Degradation of ErbB2, and This Effect Is Further Increased by Combining Pertuzumab with Trastuzumab. Pharmaceuticals 2012, 5, 674-689.

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