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

^* To whom correspondence should be addressed. 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]

Key Words: Breast cancer cells, Trastuzumab, Bortezomib, p27, NFkappaB

This article has been cited by other articles:

				R. Tongbai, G. Idelman, S. H. Nordgard, W. Cui, J. L. Jacobs, C. M. Haggerty, S. J. Chanock, A.-L. Borresen-Dale, G. Livingston, P. Shaunessy, et al. Transcriptional Networks Inferred from Molecular Signatures of Breast Cancer Am. J. Pathol., February 1, 2008; 172(2): 495 - 509. [Abstract] [Full Text] [PDF]