Synergy between BRD9- and IKZF3-Targeting as a Therapeutic Strategy for Multiple Myeloma.

Simple Summary: Multiple myeloma (MM) is an incurable disease affecting predominantly elderly people (>65 years of age). Despite improvement in the 10-year survival rate for MM patients due to the advent of medications, including immunomodulatory drugs (IMiDs) (such as pomalidomide and lenalidomide) and proteasome inhibitors, coupled with autologous stem cell transplant, more effective and safe therapies are still needed. Bromodomain-containing protein 9 (BRD9) has been shown to be important for the survival of MM cells. We discovered that drugs that block the function of BRD9 increase the effectiveness of IMiDs and can override resistance to these medications. Our findings suggest that the combined use of IMiDs and drugs that target BRD9 could potentially improve clinical outcomes for MM patients. Progress in the treatment of multiple myeloma (MM) has resulted in improvement in the survival rate. However, there is still a need for more efficacious and tolerated therapies. We and others have shown that bromodomain-containing protein 9 (BRD9), a member of the non-canonical SWI/SNF chromatin remodeling complex, plays a role in MM cell survival, and targeting BRD9 selectively blocks MM cell proliferation and synergizes with IMiDs. We found that synergy in vitro is associated with the downregulation of MYC and Ikaros proteins, including IKZF3, and overexpression of IKZF3 or MYC could partially reverse synergy. RNA-seq analysis revealed synergy to be associated with the suppression of pathways associated with MYC and E2F target genes and pathways, including cell cycle, cell division, and DNA replication. Stimulated pathways included cell adhesion and immune and inflammatory response. Importantly, combining IMiD treatment and BRD9 targeting, which leads to the downregulation of MYC protein and upregulation of CRBN protein, was able to override IMiD resistance of cells exposed to iberdomide in long-term culture. Taken together, our results support the notion that combination therapy based on agents targeting BRD9 and IKZF3, two established dependencies in MM, represents a promising novel therapeutic strategy for MM and IMiD-resistant disease. [ABSTRACT FROM AUTHOR]