A452, HDAC6-selective inhibitor synergistically enhances the anticancer activity of immunomodulatory drugs in IMiDs-resistant multiple myeloma

Multiple Myeloma (MM) is a hematological malignancy of plasma cells. Although advanced therapies have elevated MM survival rate, MM eventually relapses. Relapsed/refractory MM (R/R MM) cells gain resistance to previously used drugs, which reduces treatment options. In this study, we propose a newly synthesized HDAC6-selective inhibitor, A452, as a strategy to overcome resistance to immunomodulatory drugs (IMiDs), the principal MM therapeutic drugs. Here, we identified that A452 alone reduces the viability and growth of IMiDs-resistant cells as well as synergistically reduces viability when combined with IMiDs. We confirmed that this anticancer activity occurrs by inducing apoptosis. To determine if A452 overcomes IMiDs resistance, we checked the change in the protein level of IMiDs direct/indirect targets. As a result, the combination of A452 and IMiDs slightly increased CRBN and decreased Aiolos and Ikaros, the targets of CRBN. Moreover, A452 decreased c-Myc and IRF-4 when combined with IMiDs. These data suggest that A452 helps to overcome the resistance of IMiDs. Finally, significant synergy of anticancer activity was detected when using triple combinations of A452, IMiDs, and dexamethasone. In conclusion, the novel HDAC6-selective inhibitor A452 would be beneficial to combination therapy, including IMiDs in R/R MM as a strategy for overcoming IMiDs resistance.