Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma.
Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma.
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DOI：
10.1158/2643-3230.bcd-23-0062
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发表时间：
2024-01-08
影响因子：
11.2
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中科院分区：
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IRF4-MYC前馈超级增强子的转录调控是IMIDD抗骨髓瘤活性、合理的治疗组合和耐药机制的关键。多发性骨髓瘤(MM)是一种恶性疾病，通常由MYC引起，并由IRF4持续存在，IRF4由超级增强剂上调。IKZF1和IKZF3可与超级增强剂结合，并可通过免疫调节性亚胺类药物(IMIDs)降解。成功的IMiD反应下调了MYC和IRF4的表达；然而，这在耐IMiD的细胞中失败了。使用BET和EP300转录共激活蛋白的抑制剂也可以在耐IMiD的肿瘤中实现MYC和IRF4的下调；然而，在体内，这些药物的治疗窗口很窄。通过将IMIDS与EP300抑制相结合，我们证明了MYC和IRF4的更大下调，体外和体内对骨髓瘤的协同杀伤，以及更长的治疗窗口。有趣的是，当高水平的AP-1因子BATF维持MYC和IRF4的表达时，这种有效的组合失败了。我们的结果确定了一种有效的药物组合和以前未知的IMiD耐药机制。这些结果突显了MM对IKZF1结合的超级增强剂的依赖，通过将IMiD介导的IKZF1和IKZF3的降解与EP300抑制相结合的有效治疗组合，可以有效地针对MM。他们还发现AP-1因子是MM中一种未被认识的IMiD抵抗机制。参见Neri，Barwick等人的相关文章，第56页。见云和克利夫兰的相关评论，第5页。本文精选自本期第4页。
Transcriptional regulation of IRF4-MYC feed-forward super-enhancer is the key to IMiD antimyeloma activity, rational therapy combinations, and mechanisms of resistance. Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiD). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance. These results highlight the dependence of MM on IKZF1-bound super-enhancers, which can be effectively targeted by a potent therapeutic combination pairing IMiD-mediated degradation of IKZF1 and IKZF3 with EP300 inhibition. They also identify AP-1 factors as an unrecognized mechanism of IMiD resistance in MM. See related article by Neri, Barwick, et al., p. 56. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4