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

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-κB (NF-κB) activation and induce nuclear accumulation of the cyclin-dependent kinase inhibitor p27kip1, 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-κB 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-κB 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-κB 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]