Abstract Lysine specific demethylase-1 (LSD-1) expression correlates with poor survival in prostate cancer. LSD-1 is also key in androgen receptor signaling in androgen sensitive and castration refractory prostate cancer. LSD-1 is a chromatin modifying enzyme that in conjunction with its binding partners functions as an ‘erasor’ in the Epigenetic code process and demethylates lysine 4 and 9 residues on H3 protein resulting in gene repression or activation. Specifically in prostate cancer it demethylates H3k9me2 playing an important role in androgen receptor signaling promoting myc expression. Docetaxel chemotherapy is effective in prostate cancer but limited by toxicity and development of resistance. In this study we demonstrate synergy between LSD-1 inhibition and docetaxel in castrate refractory cell lines. We further demonstrate that LSD-1 inhibition is effective in docetaxel resistant cell lines. Cell survival assays were performed with HCI2509 on castrate refractory and docetaxel resistant prostate cancer cell lines. Histone methylation and myc expression were assessed. Colony formation assays, cell cycle analysis, xenograft studies were performed. Synergy studies were performed to assess the combination of 2509 and docetaxel. HCI2509 is cytotoxic to castrate refractory and docetaxel resistant prostate cancer cell lines in low micromolar doses. Treatment with HCI2509 resulted in dose dependent increase in H3K4me2, H3K4me3, H3K9me2 levels and decrease in myc protein. RT-PCR showed a significant decrease in MYC expression upon treatment with HCI2509. Cell cycle progression was arrested at G0/G1 upon treatment with 2509 with inhibition of colony formation at 10 to 100 fold lower concentrations. PC3 xenografts in mice showed significant reduction in tumor burden upon treatment with 2509 with increased H3K9me2 marks and reduced myc protein levels. LSD-1 inhibition with HCI2509 has therapeutic potential in castrate refractory and docetaxel resistant prostate cancer. It inhibits myc expression and sensitizes castrate refractory prostate cancer to docetaxel. Citation Format: Sumati Gupta, Alexis Weston, Jared Bearss, Sunil Sharma. Reversible lysine specific demethylase-1 inhibition is synergistic with docetaxel in castrate refractory prostate cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C91.