Tyrosine kinase inhibitors belong to an important class of drugs that inhibit ErbB2 activation and signal transduction and represent a breakthrough in the treatment of breast cancer, in which ErbB2 overexpression portends a poor prognosis and occurs in 25-30% of women with breast cancer.Our translational research has been done in ErbB2-overexpressing breast cancer cell lines, tumor xenografts, and breast cancer patients provided insight into the biological effects of lapatinib (GW572016/Tykerb) on signaling networks integral to the growth and survival of breast cancer ceils.Lapatinib is a highly selective dual inhibitor of ErbB2 (HER2) and ErbB 1 (EGFR) receptor tyrosine kinases approved for clinical use in 2007.We have found that lapatinib inhibits both EGFR and ErbB2 leading to downstream AKT and Erk1/2 pathway inhibition and down regulation of survivin, which result in growth arrest and apoptosis.This leads to deregulated growth and survival signaling.Unfortunately, the development of acquired resistance (autoresistance) to this important class of drugs significantly limits their efficacy in the clinic.Through the chronic exposure of lapatinib, we have developed cellular models of lapatinib autoresistance that mimic the daily dosing of lapatinib in patients.We have found that one mechanism of autoresistance involves a switch in the regulation of turnor cell survival from ErbB2 to the estrogen receptor (ERa).This mechanism of autoresistance was abrogated by the simultaneous blocking of ER and ErbB2 signaling using a combination of lapatinib and anti-estrogen.Identifying mechanisms of autoresistance has successfully provided the scientific rationale for testing combination therapies in clinical to improve clinical outcomes in women with breast cancer.