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e14104 Background: TNF-related apoptosis-ligand (TRAIL) can selectively induce apoptosis in cancer cells without causing damage to normal cells. However, some tumors are resistant to TRAIL monotherapy and clinical studies assessing targeted agents towards the TRAIL receptor have failed to show robust therapeutic activity. A number of studies have reported that the combination of targeted agents against the TRAIL receptor with standard systemic therapy and another targeted therapy considerably increased anti-tumor activity in experimental NSCLC models. Polo like kinase 1 (PLK1) is an emerging anti-mitotic target for NSCLC with high selectivity. Depleting PLK1 has been shown to reduce cell proliferation and induce apoptosis in NSCLC cells but not in normal cells. Both PLK1 and TRAIL-induced apoptosis pathways are important in supporting the malignant phenotype. We postulated that inhibiting PLK1 could enhance TRAIL-induced apoptosis. We therefore combined human recombinant TRAIL (rhTRAIL) and the PLK1 inhibitor RO3280, and studied the effect of combinatorial treatment on NSCLC cells. Methods: Cell growth was assessed by MTS assay and apoptotic activity by FACS and western blot analysis. The effect of combinatorial treatment on MAPK/ERK, PI3K/Akt and JAK/STAT signaling pathways that play an essential role in the survival of NSCLC cells were investigated by western blot analysis. Results: In this study, we demonstrate that the combination of a rhTRAIL with RO3280 synergistically reduces cell growth and strongly increases apoptotic activity in NSCLC cells. In response to RO3280 treatment, STAT3 activity is inhibited, possibly contributing to the sensitization of NSCLC cells to TRAIL-induced apoptosis. Blockade of STAT3 activity with a STAT3 inhibitor (stattic) and siRNA-mediated knockdown of STAT3 significantly enhances TRAIL-induced apoptosis in NSCLC cells. Conclusions: Our results suggest that this synergistic effect might occur through the inhibition of STAT3 activity which in turn may further contribute to the sensitization of the NSCLC cells to TRAIL therapy. Taken together, our results support the further exploration of PLK1 inhibitors in combination with TRAIL therapy in the treatment of NSCLC.