Small-molecule HDAC and Akt Inhibitors Suppress Tumor Growth and Enhance Immunotherapy in Multiple Myeloma

Background: Multiple myeloma (MM) patients may undergo relapse and experience resistance to existing therapies. Cereblon (CRBN) is key mediator of the bioactivities of immunomodulatory drugs (IMiDs), including lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patients and considered to contribute to IMiD resistance. Thus, overcoming resistance to drugs, including IMiDs, is expected to improve clinical outcomes. Here, we examined potential mechanisms of a histone deacetylase (HDAC) inhibitor and Akt inhibitor in treatment of relapsed/refractory MM patients. Methods: We established lenalidomide-resistant cells by knocking down or knocking out CRBN in MM cells. Additionally, we derived multi-drug (bortezomib, doxorubicin, or dexamethasone)-resistant cell lines and primary cells from relapsed/refractory MM patients. The effects of HDAC and Akt inhibitors on these drug-resistant MM cells were then observed with a particular focus placed on whether HDAC inhibitors enhance immunotherapy efficacy. We also investigated the effect of lenalidomide on CRBN-deficient cells. Results: HDAC inhibitor suppressed the growth of drug-resistant MM cell lines, and enhanced antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies by upregulating natural killer group 2D (NKG2D) ligands in MM cells. CRBN-deficient cells showed lenalidomide-induced upregulation of glycogen synthase kinase-3 (p-GSK-3) and c-Myc phosphorylation. Meanwhile, HDAC and Akt inhibitors downregulated c-Myc by blocking GSK-3 phosphorylation. HDAC and Akt inhibitors also exhibited synergistic cytotoxic and c-Myc–suppressive effects. Moreover, the dual HDAC and PI3K inhibitor, CUDC-907, exhibited cytotoxic and immunotherapy-enhancing effects for MM cells, including for multi-drug-resistant lines and primary cells including lenalidomide-resistant patients. Conclusions: Combined HDAC and Akt inhibition represents a promising approach for the treatment of relapsed/refractory MM.