Bortezomib (PS-341, Velcade) increases the efficacy of trastuzumab (Herceptin) in HER-2-positive breast cancer cells in a synergistic manner.
Mol Cancer Ther. 2006 Dec 5
Cardoso F, Durbecq V, Laes JF, Badran B, Lagneaux L, Bex F, Desmedt C, Willard-Gallo K, Ross JS, Burny A, Piccart M, Sotiriou C.
Translational Research Unit and Laboratory of Experimental Hematology, Bordet Institute; Laboratoire de Microbiologie, Center for Education and Research in Food and Chemical Industry, Universite libre de Bruxelles, Brussels, Belgium; and Albany Medical College, Albany and Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts.
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-kappaB (NF-kappaB) 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-kappaB 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-kappaB 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-kappaB 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]. |
