Abstract 5534: A novel and oral histone deacetylase inhibitor, resminostat, effectively suppresses the growth of non-small cell lung cancer in a xenograft mouse model

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Accumulating evidence reveals effectiveness of histone deacetylase (HDAC) inhibition in various types of cancer, and resminostat is a novel and oral HDAC inhibitor. In this study, we investigated the preclinical activity of resminostat in human non-small-cell lung cancer (NSCLC) cells, especially in combination with docetaxel (DTX). Materials and Methods: Anti-proliferative activity of resminostat was evaluated in 9 human NSCLC cell lines in vitro. Monolayers of cultured cells were exposed to resminostat and cell viability was determined. The amount of p21, acetylated histone H3 and α-tublin were analyzed by Western blotting in NCI-H460 cells exposed to resminostat. In addition, caspase-3 activity was measured. In a drug combination study, cells were simultaneously exposed to resminostat and DTX, and the synergistic effects of this drug combination were analyzed using the Combination Index, calculated by the median-effect method. For in vivo studies, a suspension of NCI-H460 cells was subcutaneously inoculated into the flank of male nude mice. The antitumor efficacies of oral resminostat alone or in combination with intravenous DTX were evaluated in this NSCLC xenograft model. Results: Resminostat exhibited antiproliferative activity in all tested cell lines. Sensitivity to resminostat was not influenced by the genetic status of KRAS among the cell lines (IC50 from 9 cell lines: 0.4-8.7 μmol/L). The treatment of cells with resminostat alone increased the levels of total p21 protein and acetylated histone H3. α-tublin was also acetylated by resminostat treatment and the level of acetylation was enhanced by the combination treatment with DTX. The amount of polymerized α-tubulin was increased by DTX treatment and this effect was greater in the combination treatment with resminostat than with DTX alone. Caspase-3 was more significantly activated by the combination treatment than with each mono-treatment. The Combination Index showed synergistic or additive effects in the resminostat plus DTX combination. The antitumor activities of resminostat were demonstrated in NCI-H460 tumor-bearing mice, where an up-regulation of p21 was accompanied by acetylation of histone H3 in the tumor tissues. The tumor growth inhibition ratio (IR) in the combination treatment was 2.6 and 1.8 times higher than with DTX alone or with resminostat alone, respectively, following a tolerable drug application schedule. Conclusion: These results demonstrated the potent activity of resminostat in NSCLC. The combination of resminostat and DTX appears to be a promising regimen to be tested in clinical trials in NSCLC patients. Based on this study, we initiated a phase I/II study in NSCLC patients to examine the safety and efficacy of this combination. Citation Format: Akimitsu Takagi, Hiroaki Konishi, Momomi Tsugane, Keisuke Taniguchi, Hiroyuki Takahashi, Yu Inutake, Akinobu Watanabe, Hiroshi Kodaira, Takeshi Matsuzaki. A novel and oral histone deacetylase inhibitor, resminostat, effectively suppresses the growth of non-small cell lung cancer in a xenograft mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5534. doi:10.1158/1538-7445.AM2014-5534