The novel β2-selective proteasome inhibitor LU-102 synergizes with bortezomib and carfilzomib to overcome proteasome inhibitor resistance of myeloma cells

Proteasome inhibitor resistance is a challenge for myeloma therapy. Bortezomib targets the beta 5 and beta 1 activity, but not the beta 2 activity of the proteasome. Bortezomib-resistant myeloma cells down-regulate the activation status of the unfolded protein response, and up-regulate beta 2 proteasome activity. To improve proteasome inhibition in bortezomib- resistant myeloma and to achieve more efficient UPR activation, we have developed LU-102, a selective inhibitor of the beta 2 proteasome activity. LU-102 inhibited the beta 2 activity in intact myeloma cells at low micromolar concentrations without relevant co-inhibition of beta 1 and beta 5 proteasome subunits. In proteasome inhibitor-resistant myeloma cells, significantly more potent proteasome inhibition was achieved by bortezomib or carfilzomib in combination with LU-102, compared to bortezomib/carfilzomib alone, resulting in highly synergistic cytotoxic activity of the drug combination via endoplasmatic reticulum stress-induced apoptosis. Combining bortezomib/carfilzomib with LU-102 significantly prolonged proteasome inhibition and increased activation of the unfolded protein response and IRE1-alpha activity. IRE1-alpha has recently been shown to control myeloma cell differentiation and bortezomib sensitivity (Leung-Hagesteijn, Cancer Cell 24: 3, 289-304). Thus, beta 2-selective proteasome inhibition by LU-102 in combination with bortezomib or carfilzomib re-sults in synergistic proteasome inhibition, activation of the unfolded protein response, and cytotoxicity, and overcomes bortezomib/carfilzomib resistance in myeloma cells in vitro.