Ixabepilone (BMS-247550) plus trastuzumab combination chemotherapy induces synergistic antitumor efficacy in HER2 dependent breast cancers and is accompanied by modulation of molecular response markers

Abstract

561 Background: Ixabepilone (Ixa) belongs to a class of structurally novel, microtubule-stabilizing agents that exert their antimitotic action by binding to tubulin with a binding mode that is distinct from the taxanes. Ixa is non-cross-resistant with the taxanes in preclinical human primary tumor models. In Phase II trials Ixa exhibited robust activities in breast cancers, with or without prior taxanes. Here we determined the activity of combined treatment with Ixa plus trastuzumab in preclinical breast cancer models, and identified potential pharmacogenomic correlates that predict responsiveness to the trastuzumab/Ixa combination Methods: BT474 and KPL-4 human breast cancer cell lines were used; both express the receptor tyrosine kinase HER2 and are dependent on HER2 signalling for growth. Effects of drug treatments in vitro were determined by a vital dye uptake assay (MTS) or a colony formation assay. In vivo, BT474 and KPL4 were grown as SC tumors in mice. Gene expression profiling was performed using...