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.
多发性骨髓瘤（MM）的治疗进展已使患者生存率得到提升，但临床上仍需更有效且耐受性良好的疗法。我们与其他研究团队发现，含溴结构域蛋白9（BRD9）作为非经典SWI/SNF染色质重塑复合物的成员，在MM细胞存活中发挥重要作用；靶向BRD9能选择性阻断MM细胞增殖，并与免疫调节药物（IMiDs）产生协同效应。研究发现，这种体外协同作用与MYC及Ikaros蛋白家族（包括IKZF3）的下调相关，而过表达IKZF3或MYC可部分逆转协同效应。RNA-seq分析显示，协同作用与MYC及E2F靶基因相关通路的抑制有关，涉及细胞周期、细胞分裂和DNA复制等过程；同时细胞黏附、免疫及炎症反应通路被激活。重要的是，联合应用IMiD治疗与BRD9靶向干预能下调MYC蛋白并上调CRBN蛋白水平，从而逆转长期培养中细胞对伊伯度胺的耐药性。综上所述，本研究证实针对MM两个关键依赖因子BRD9与IKZF3的联合靶向治疗，为MM及其IMiD耐药患者提供了一种前景广阔的新型治疗策略。
Synergy between BRD9- and IKZF3-Targeting as a Therapeutic Strategy for Multiple Myeloma
肿瘤(癌症)患者之家