Multiple myeloma cell lines expression profile of OTX015-treated cells compared to DMSO controls

Several studies demonstrate that the bromodomain inhibitor OTX015 has preclinical antitumor activity in a variety of solid tumors and hematologic cancers. However, translation of these data to molecules suitable for clinical development has not yet to be accomplished in multiple myeloma (MM). Here, we identified genes and biologic processes that underpin the antimyeloma activity of OTX015 with global transcriptomics. OTX015 exerted strong antiproliferative effect and induced cell cycle arrest in vitro. Gene expression profiling showed that OTX015 targeted NF-κB, EGFR, cell cycle regulation, cancer proliferation signaling pathway. Gene expression signatures associated with different sensitivity to OTX015 were also identified. The data also showed that oral administration of OTX015 displayed significant antitumor activity in mice model of disseminated human myeloma. In addition, our study provided the first evidence and rationale that OTX015 could promoted osteoblast differentiation of mesenchymal stem cells (MSCs) and inhibited osteoclast formation and resorption in vivo experiments. Herein we expanded the mechanistic understanding of BET inhibitors OTX015 in MM. Our preclinical studies provided a strong rationale for extending the clinical testing of the novel antimyeloma agent OTX015 and revealed insights into biologic pathways required for myeloma cell proliferation. OTX015 induced gene expression in multiple myeloma cell lines was measured at 72 hours after drug exposure