e16555 Background: Endometrial carcinoma (EC) frequently shows deregulation of the extrinsic apoptotic pathway. One of the critical regulators of apoptosis resistance in EC is FLIP, under the control of NFkB and a cellular complex composed of CK2, KSR1, and BRAF. Methods: Four different EC cell lines, which are known to exhibit resistance to TRAIL/FAS-induced apoptosis (Ishikawa, KLE, HEC1A, and RL-95) were exposed to various pharmacologic substances that target proteins involved in the regulation of the extrinsic apoptotic pathway and receptor tyrosine kinases including bortezomib, sorafenib, sunitinib, DRB, apigenin, MG-132, epoxomicin, and ALLN. Moreover, EC cell lines were subjected to down-regulation of several of these genes (FLIP, CK2, KSR1, and BRAF) by shRNA. Cell viability and apoptotic morphology was determined. Results were validated in tumor cell explants. Results: Bortezomib induced cell death on EC cells and primary explants to a 70% extent. However, 100% of treated explants and cell lines activated NF-kB instead of blocking its transcriptional potential. Combination of sunitinib plus bortezomib induced 75% fold reduction in NFkB activity and induced a 5% of synergistic increse of apoptotic cell death in Ishikawa cells. Treatment of the four cell lines with TRAIL failed to induce cell death. However, FLIP knock-down sensitized the cells to TRAIL-induced apoptosis (80%). Moreover, down-regulation of CK2, KSR1, and BRAF by pharmacological inhibition, or shRNA, reduced FLIP cellular levels, and induced TRAIL-dependent apoptosis in 70%-100% of EC cell lines tested. Sorafenib induced a dose-dependent cell death in all four cell lines, to a 70%-100% extent at 48 hours. Conclusions: In vitro pharmacologic targeting of the apoptotic pathway effectively induces cell death in EC cell lines. These findings justify clinical trials with these agents in EC. [Table: see text]