Multiple myeloma (MM) is a plasma cell malignancy considered incurable despite the recent therapeutic advances. Effective targeted therapies are therefore needed. Our previous studies proved that inhibiting CDK7 impairs the cell cycle and metabolic programs by disrupting E2F1 and MYC transcriptional activities, making it an appealing therapeutic target for MM. Given that CDK7 and BRD4 operate in two distinct regulatory axes in MM, we hypothesized that targeting these two complementary pathways simultaneously would lead to a deeper and more durable response. Indeed, combination therapy had superior activity against MM cell growth and viability, and induced apoptosis to a greater extent than single-agent therapy in both cell lines and patient cells. This synergistic activity was also observed in Waldenström's Macroglobulinemia (WM) cells and with other inhibitors of E2F1 activity. Dual inhibition effectively impaired the MYC and E2F transcriptional programs and MM tumor growth and progression in xenograft animal models, providing evidence for combination therapy's potential as a therapeutic strategy in MM and WM.

中文翻译：

---

释放选择性 CDK7 和 BRD4 抑制对多发性骨髓瘤细胞生长的治疗潜力。


多发性骨髓瘤 （MM） 是一种浆细胞恶性肿瘤，尽管最近的治疗取得了进展，但人们认为无法治愈。因此，需要有效的靶向治疗。我们之前的研究证明，抑制 CDK7 通过破坏 E2F1 和 MYC 转录活性来损害细胞周期和代谢程序，使其成为 MM 的一个有吸引力的治疗靶点。鉴于 CDK7 和 BRD4 在 MM 中在两个不同的调节轴上起作用，我们假设同时靶向这两个互补途径将导致更深入、更持久的反应。事实上，联合疗法对 MM 细胞生长和活力具有优异的活性，并且在细胞系和患者细胞中都比单药疗法更大程度地诱导细胞凋亡。在 Waldenström 巨球蛋白血症 （WM） 细胞和其他 E2F1 活性抑制剂中也观察到这种协同活性。双重抑制在异种移植动物模型中有效损害了 MYC 和 E2F 转录程序以及 MM 肿瘤的生长和进展，为联合疗法作为 MM 和 WM 治疗策略的潜力提供了证据。