Abstract 4051: Combination efficacy of HDAC inhibitor vorinostat and CDK-4/6 dual inhibitor palbociclib against therapy-resistant mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma accounting for about 7% of all non-Hodgkins lymphoma. While multiple therapy regimens are available to treat MCL patients, ultimately relapse from therapy-resistant MCL, making MCL carry the worst prognosis of all B cell lymphomas. Emerging evidence suggest that, dysregulated histone deacetylases (HDACs) and the key molecules of cell cycle regulator cyclin-dependent kinases (CDKs) have been shown to be commonly associated with many lymphomas including MCL, and are considered as promising targets for relapsed lymphoma therapy. Several inhibitors of these target pathways/molecules are in clinical trials as monotherapies or in combination with other anticancer agents. Therefore, in this study, we investigated the single agent and combination efficacies of the HDACs inhibitor vorinostat, and CDK-4/6 dual inhibitor palbociclib on MCL cell growth/survival and underlying molecular mechanism(s) using different MCL cell lines (Granta 519, Jeko-1 and JVM-2) including therapy-resistant MCL cell lines derived from Granta-519 (GRL, GRK and GRR). We used MTT assay to measure the survival and proliferation, agar colony formation assay to determine the effects of these inhibitors on the anchorage independent growth, Annexin-V analyses to examine the cells undergoing apoptosis following treatments and western blot analyses to determine the expression levels of target molecules including pRb, histone acetylation, cyclin-D1 and Bcl-2. The concentration of these inhibitors used in this study were similar to the published literature including sub-IC50 levels determined in our laboratory. Our results showed that both inhibitors as single agents or combined, significantly suppressed the cell growth, and induced apoptosis in therapy-resistant and other MCL lines in vitro. The single agent and combined anti-lymphoma efficacies of these inhibitors were further confirmed with the colony formation ability of the MCL cells grown in 0.3% agar semisolid media. In addition, combination of vorinostat and palbociclib treatment significantly inhibited the activation of phosphorylated-retinoblastoma (pRb) protein, a key molecule of cell cycle and increased the expression of acetylated-Histone H3 (H3-Ac) as determined by western blot analyses. Subsequently, the expression of Cyclin D1 (proliferation, MCL hallmark) and anti-apoptotic Bcl-2 proteins were also downregulated by these inhibitors. Together, our findings suggest that combination of vorinostat and palbociclib showed a significant synergistic anti-MCL activity by targeting associated pathways/molecules. This targeted approach warrants further preclinical evaluation for translation to the clinic. Citation Format: Nagendra K. Chaturvedi, Nathan D. Hatch, Garrett L. Sutton, Matthew J. Kling, Julie M. Vose, Shantaram S. Joshi. Combination efficacy of HDAC inhibitor vorinostat and CDK-4/6 dual inhibitor palbociclib against therapy-resistant mantle cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4051. doi:10.1158/1538-7445.AM2017-4051