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-kappa B (NF-kappa B) activation and induce nuclear accumulation of the cycl in-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-kappa 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-kappa 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-kappa 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.