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Research Articles: Therapeutics, Targets, and Development

Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2–positive breast cancer cells in a synergistic manner

¹ Translational Research Unit and ² Laboratory of Experimental Hematology, Bordet Institute; ³ Laboratoire de Microbiologie, Center for Education and Research in Food and Chemical Industry, Université libre de Bruxelles, Brussels, Belgium; and ⁴ Albany Medical College, Albany and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts

Requests for reprints: Fatima Cardoso, Department of Medical Oncology, Jules Bordet Institute, Boulevard de Waterloo, 125, 1000 Brussels, Belgium. Phone: 32-2-541-3082; Fax: 32-2-538-08-58. E-mail: fatima.cardoso{at}bordet.be

Abstract

Background: Preclinical and clinical studies have shown that the proteasome inhibitor bortezomib (PS341, Velcade) is highly effective when combined with chemotherapeutic agents. The value of trastuzumab (Herceptin) in HER-2–positive (3+ score by immunohistochemistry or fluorescence in situ hybridization positive) breast cancer is also known; however, the response rate is <40% for metastatic breast cancer. These two pharmacologic agents prevent nuclear factor-B (NF-B) activation and induce nuclear accumulation of the cyclin-dependent kinase inhibitor p27^kip1, suggesting that combining bortezomib with trastuzumab could increase trastuzumab efficacy. Methods: Drug cytotoxicity, both individually and together, and drug effects on p27 localization and NF-B activation were investigated on four breast cancer cell lines: SKBR-3 (HER-2⁺⁺⁺), MDA-MB-453 (HER-2⁺⁺), HER-2–transfected MCF-7 (HER-2⁺⁺⁺), and MCF-7 (HER-2^–). Results: Bortezomib induced apoptosis in HER-2–positive and HER-2–negative breast cancer cells in a dose- and time-dependent manner. Together, these drugs induced apoptosis of HER-2^++/+++ cells at low concentrations, which had no effect when used alone, indicating there was a synergistic effect. Sequential treatment (trastuzumab then bortezomib) induced either necrosis or apoptosis, depending on the trastuzumab preincubation time. Susceptibility to bortezomib alone and the drug combination correlated with NF-B activity and p27 localization. Conclusions: The addition of bortezomib to trastuzumab increases the effect of trastuzumab in HER-2^+++/++ cell lines in a synergistic way. This effect likely results from the ability of these two drugs to target the NF-B and p27 pathways. The potential clinical application of this drug combination is under current evaluation by our group in a phase 1 clinical trial. [Mol Cancer Ther 2006;5(12):3042–51]

Grant support: Belgian nonprofit organization Fondation Lambeau-Marteaux, Millennium Pharmaceuticals, and Belgian Fonds National de la Recherche Scientifique grants FRSM N°3.4584.01 and Télévie 7.4580.04.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: C. Desmedt is a doctoral fellow of the Fonds National de la Recherche Scientifique-Télévie. B. Badran is a postdoctoral fellow of the Fonds National de la Recherche Scientifique. K. Willard-Gallo is a scientific collaborator of the Fonds National de la Recherche Scientifique-Télévie. J.S. Ross is a Scientific Fellow at Millennium Pharmaceuticals, Inc.

Conflict of interest statement: The authors have received a research grant from Millennium Pharmaceutics, Inc. to conduct translational research studies with Bortezomib.

Received 2/23/06; revised 10/12/06; accepted 10/30/06.

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