Abstract 275: Combining low dose microtubule targeting agents with belinostat potentiates cytotoxic response in HDACi resistant diffuse large b-cell lymphoma

Abstract

Abstract Patients diagnosed with Diffuse Large B-cell lymphoma have an overall 60% five-year survival rate. New therapeutic approaches are needed to effectively treat aggressive forms of DLBCL that are refractory to the standard treatment or that relapse within two years of treatment. Histone deacetylase inhibitors (HDACi) are novel therapeutics that are well tolerated in humans and are being extensively evaluated in combination with other therapeutics against hematologic malignancies. Rational selection of companion therapeutics has been difficult due to the cell type-specific mechanisms of HDACi action. In order to address this, we have developed a pre-clinical model system of sensitivity and resistance to HDACi-induced cytotoxicity in DLBCL cell lines that share characteristics with aggressive DLBCL tumors. We previously reported that HDACi resistance is associated with reversible arrest in G1 that involves sustained up-regulation of cyclin-dependent kinase inhibitors. In the current study we demonstrate that HDACi-sensitive cell lines undergo mitotic arrest prior to anaphase in response to treatment with the approved HDACi, belinostat, consistent with activation of the spindle assembly checkpoint (SAC). In contrast, HDACi-resistant cell lines are capable of completing mitosis in the presence of belinostat. To force SAC activation in HDACi resistant cell lines, we used low dose microtubule targeting agents (MTA) vincristine and paclitaxel to induce maximal mitotic arrest with minimal cytotoxicity. The combination of these low dose MTAs and belinostat efficiently caused SAC failure, mitotic slippage, and apoptosis in a synergistic manner. A key mechanism associated with resistance to MTAs is their ability to induce aneuploid cell populations that survive and undergo endoreduplication. The addition of belinostat eliminated the accumulation of a vincristine-induced aneuploid population. Pan-caspase inhibition in conjunction with belinostat and vincristine co-treatment resulted in a sustained survival of the aneuploid population. Thus belinostat triggers apoptosis in the aneuploid cells to enhance the cytotoxic effects of vincristine. Our study identifies the use of low dose MTA/HDACi combination as a potential therapeutic strategy for treatment of relapsed or refractory DLBCL. Citation Format: Aaron P. Havas, Anvi Bhakta, Kameron Rodrigues, Catharine L. Smith. Combining low dose microtubule targeting agents with belinostat potentiates cytotoxic response in HDACi resistant diffuse large b-cell lymphoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 275.