e13579 Background: BRCA1-deficiency confers sensitivity to PARP1 inhibition (alone or in combination with platinum compounds) in triple-negative breast cancer (TNBC). Recent understanding of the biology of TNBC tumor cells has recognized molecular targets suitable for treatment with targeted therapeutics including cell surface RTK(s), such as EGFR. Methods: We studied the effect of combination of PARP inhibitor, (olaparib) plus carboplatin with a dual EGFR/VEGFR inhibitor, vandetanib in a TNBC model in both in vitro and in vivo settings. We tested the effects of drug combinations on (a) cell signaling marker(s) of survival/proliferation/apoptosis, (b) adhesion-dependent and clonogenic survival, and (c) different phenotypes (migration, invasion, vascular mimicry, and cord formation) using TNBC cell and HUVEC cells. The combination of PARP1 inhibition and EGFR/VEGFR inhibition was evaluated in tumor-bearing athymic mice treated with olaparib plus carboplatin and vandetanib. Results: Data showed that, (1) EC50s for vandetanib ranged from 5-15 µM, (2) vandetanib (10 µM) inhibited phosphorylation of AKT (S473 & T308), S6RP, 4EBP1 and ERK, (3) effect of olaparib on TNBC cell survival can be effectively studied in vitro by clonogenic assay, (4) TNBC cell lines exhibited higher sensitivity to vandetanib in clonogenic assay when combined with 10 µM fixed dose of olaparib, and (5) a combination of vandetanib with olaparib plus carboplatin time dependently increased caspase-3 and PARP cleavage, inhibited vascular mimicry, blocked fibronectin-directed migration, and suppressed clonogenic growth in TNBC cells.Vandetanib blocked (a) cord formation, (b) vitronectin-directed migration, and (c) HIF-1alpha accumulation and phosphorylation of proliferation markers (AKT, 4EBP1, and ERK) in HUVEC cells. Conclusions: Anti-proliferative/pro-apoptotic, and anti-migratory/invasive effects of vandetanib (alone or in combination with carboplatin plus olaparib) were observed both in tumor cells and in endothelial cells. We are currently studying in vivo the effect of combining olaparib plus carboplatin with vandetanib, in xenograft model the results of which will be presented in the meeting.