Dual CARM1-and IKZF3-targeting: A novel approach to multiple myeloma therapy synergy between CARM1 inhibition and IMiDs.

Abstract

Advancements in the treatment of multiple myeloma (MM) have resulted in an improvement in the survival rate. However, there continues to be an urgent need for improved therapies. The protein arginine methyltransferase, CARM1 (coactivator associated arginine methyltransferase 1), is emerging as a potential cancer therapy target and inhibitors have been developed. MM cell lines are particularly dependent on CARM1 for cell survival. Here, we show that targeting of CARM1 through small molecule inhibition potentiates the activity of immunomodulatory drugs (IMiDs) in cell line models of MM. This likely occurs through synergistic targeting of Aiolos (IKZF3) and MYC expression. Rational design of a new molecule, 074, which consists of a CARM1 inhibitor linked to the IMiD pomalidomide, was carried out and treatment with this agent led to more potent killing of MM cells than either the CARM1 inhibitor or the IMiD as single agents. Importantly, 074 was able to override IMiD resistance. Taken together, our results demonstrate that dual CARM1/IKZF3-targeting agents represent a promising novel therapeutic strategy for MM and IMiD-resistant disease.