UAE inhibition overcomes drug resistance and enhances chemosensitivity. (A) Bone marrow plasma cells were purified from 8 previously treated myeloma patients, exposed to different doses of TAK-243 for 72 hours, and their viability was evaluated using a tetrazolium-based assay. (B) A panel of drug-resistant myeloma cell lines was compared with their drug-sensitive controls for their susceptibility to TAK-243. The panel included doxorubicin-resistant RPMI 8226/DOX 40 cells, melphalan-resistant RPMI 8226/LR-5 cells, lenalidomide-resistant MM1.S/R10R cells, dexamethasone-resistant MM1.R cells, and bortezomib-resistant KAS-6/1 V10R cells. (C) TAK-243 alone (at the indicated concentrations on the top axes), and either panobinostat (left panel) alone (PAN; at the indicated concentrations on the bottom axis) or lenalidomide (right panel) alone (LEN; at the indicated concentrations on the bottom axis) were added to U266 cells. Also, TAK-243 at the concentrations indicated in the legend was combined with either panobinostat or lenalidomide at the drug concentrations indicated in the lower abscissas to determine whether additive or synergistic interactions were seen during 72-hour drug exposures.