Abstract 2749: YM155, a small molecule survivin suppressant, sensitizes human B-cell non-Hodgkin lymphoma to rituximab-induced apoptosis

Survivin is a member of the inhibitor of apoptosis (IAP) family of proteins, and is highly expressed in various tumor types. Given its preferential expression in tumor cells, and its ability to block apoptosis and regulate cancer cell proliferation, survivin appears to be an attractive target for cancer therapy. YM155 is a small molecule survivin suppressant and shows in vitro antiproliferative activity against the broad spectrum of human cancer cell lines, including B-cell non-Hodgkin lymphoma (B-NHL). The continuous infusion of YM155 induced the tumor regression in B-NHL xenograft mice models. Furthermore, our recent study indicated that the combination treatment of YM155 and rituximab induced significant tumor growth inhibition and tumor regression without weight loss. In the present study, we examined the in vitro combination efficacy of YM155 and rituximab, and its underlying signaling pathways involved in the combination effect of YM155 and rituximab. The combination of YM155 at 1 nmol/L and rituximab at 2 ug/mL induced higher sub G1 compared with each single treatment in WSU-DLCL-2 and SU-DHL-4. Rituximab at 2ug/mL decreased phospho-STAT3 level, meanwhile, did not decreased phospho-p38 MAPK and phospho-AKT levels in WSU-DLCL-2 and SU-DHL4. To further characterize the growth inhibitory effect of inactivation of STAT3 pathway, we investigated the cell growth inhibition by AG490, a JAK2 inhibitor and STA-21, a STAT3 dimerization inhibitor in WSU-DLCL-2 and SU-DHL4. The treatment of AG-490 or STA-21 decreased cell viability in dose-dependent manner. Furthermore, the combination of YM155 at 1 nmol/L and AG490 at 10μmol/L or STA-21 at 6μmol/L induced higher apoptosis rate that was evident by the sub G1 fraction and annexin-V induction compared with each single treatment. These results suggested that the growth of human B-NHL is STAT3 dependent manner and the inhibition of STAT3 pathway sensitizes human B-NHL to YM155 induced apoptosis. The present study suggested that survivin suppression by YM155 and the convergence of disabling inhibition of STAT-dependent survival pathway by ritximab would contribute the synergistic combination efficacy. A phase 2 study with YM155 plus rituximab is ongoing in relapsed patients with diffuse large B cell lymphoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2749. doi:1538-7445.AM2012-2749