IMiDs Synergize with EP300 Inhibition to Disrupt the Ikzf/MYC/IRF4 Axis in Multiple Myeloma

Multiple myeloma (MM) is a heterogeneous plasma cell malignancy for which current therapies eventually fail. In myeloma, endogenous and translocated superenhancers drive the expression of the lineage-defining transcription factor IRF4 and oncogene MYC, respectively - both considered "undruggable". Successful standard-of-care immunomodulatory imide drugs (IMiDs) degrade superenhancer-binding pioneer factors IKAROS and AIOLOS; however, depletion of IKAROS and AIOLOS does not always correlate with a successful IMiD response, and patients treated with IMiDs ultimately relapse. We show responses to the IMiD Pomalidomide (POM) are directly correlated with downregulation of IRF4 and MYC. In IMiD-resistant cells and tumors, IRF4 and MYC downregulation could be achieved with novel coactivator-targeting drugs including the BET inhibitor JQ1 and the CBP/EP300 inhibitor GNE-781, but these were toxic and lacked a therapeutic window in vivo. We show how POM combined with GNE781 synergize and downregulate MYC and IRF4 levels, killing myeloma cells in vitro and in vivo. However, resistance to this combination was induced by expression of the AP-1 factor BATF, which directly maintained IRF4 expression and myeloma cell survival. These results identify a potent therapeutic combination and a hereto unrealized mechanism of IMiD resistance in multiple myeloma.