130 Background: Primary and acquired resistance to endocrine therapy in advanced breast cancer presents a significant barrier to maximizing the clinical effectiveness of these agents. We recently reported in a randomized, placebo controlled phase II study that entinostat (ENT), a class 1 selective HDAC inhibitor, combined with exemestane extended PFS and OS in postmenopausal women with ER+ positive breast cancer that had progressed on a prior nonsteroidal aromatase inhibitor. Likewise, everolimus (EVE), a mTORi, combined with exemestane or tamoxifen (TAM) also significantly extended PFS in a similar patient population. In order to determine the potential benefit of combining ENT with EVE plus hormone therapy we have piloted a series of xenograft studies in primary human tumor models of TAM sensitivity and resistance. Methods: Athymic nude mice bearing xenografts of tissue derived directly from patient tumors (MaCa4049 – TAM sensitive; MaCa3366/TAM – TAM resistant) were treated with A) vehicle B) 2 mg/kg EVE C) 2 mg/kg EVE + 10 mg/kg TAM D) 15 mg/kg ENT E) 2 mg/kg EVE + 10 mg/kg TAM + 15 mg/kg ENT. Tumor samples taken at the end of the study were cryoconserved for analysis of gene and protein expression and protein phosphorylation. Results: Growth of MaCa4049 tumors was inhibited in all treatment groups relative to vehicle in two independent studies conducted in this tumor model. Groups B, C and D demonstrated a similar level of activity while maximal inhibition was observed in Group E. All treatments were generally well tolerated with weight loss similar in groups C and E. Treatment of MaCa3366/TAM tumors is ongoing with similar levels of tumor growth inhibition in all groups observed relative to vehicle at week 7. Analysis of tumor samples from completed studies will be presented to provide insight into mechanism of action for the enhanced activity observed with the triple combination. Conclusions: Preclinical data demonstrating enhanced activity of entinostat combined with everolimus and hormone therapy provides the rationale for clinical investigation of this novel therapeutic approach to targeting hormone therapy resistance.