Autoresistance to ErbB2 kinase inhibitors: Elucidating mechanisms and identfying strategies to prevent its onset in breast cancer

2075 Background: Clinical efficacy of ErbB1/ErbB2 kinase inhibitors is limited by the development of acquired autoresistance. Developing clinically relevant models to study the mechanism(s) of acquired autoresistance will identify therapeutic strategies to prevent its onset. Methods: BT474 cells, an ErbB2-overexpressing/ER+ breast cancer line sensitive to lapatinib-induced apoptosis were chronically exposed to lapatinib, simulating chronic administration of lapatinib in the clinic. Lapatinib-resistant cells (rBT474) and single cell clones were established. Baseline gene expression in parental BT474 and rBT474 cells was compared using Human Affymetrix oligonucleotide arrays. Sequential tumor biopsies were analyzed by quantitative IHC as part of a clinical trial using lapatinib monotherapy (1500mg/d) in patients with metastatic breast cancer. Results: Gene expression and protein analysis indicates that acquired resistance to lapatinib is mediated by increased estrogen receptor (ER) signaling rather than los...