Multiple myeloma (MM) remains incurable despite recent therapeutic advances. RAS mutations are frequently associated with relapsed/refractory disease. Efforts to target the mitogen-activated protein kinase (MAPK) pathway with the MEK inhibitor, trametinib (Tra) have been limited by toxicities and the development of resistance. Dexamethasone (Dex) is a corticosteroid commonly used in clinical practice, to enhance efficacy of anti-myeloma therapy. Therefore, we hypothesised that the combination of Tra and Dex would yield synergistic activity in RAS-mutant MM. The response of human MM cell lines to drug treatment was analysed using cell proliferation assays, Western blotting, Annexin V and propidium iodide staining by flow cytometry and reverse phase protein arrays. The efficacy of trametinib and dexamethasone treatment in the MM.1S xenograft model was assessed by measuring tumor volume over time. The Tra/Dex combination demonstrated synergistic cytotoxicity in KRASG12A mutant lines MM.1S and RPMI-8226. The induction of apoptosis was associated with decreased MCL-1 expression and increased BIM expression. Reverse phase proteomic arrays revealed suppression of FAK, PYK2, FLT3, NDRG1 and 4EBP1 phosphorylation with the Tra/Dex combination. Notably, NDRG1 expression was associated with the synergistic response to Tra/Dex. MM cells were sensitive to PDK1 inhibition and IGF1-induced signalling partially protected from Tra/Dex treatment, highlighting the importance of this pathway. In the MM.1S tumor xenograft model, only the combination of Tra/Dex resulted in a significant inhibition of tumor growth. Overall Tra/Dex demonstrates antiproliferative activity in RAS-mutant MM cell lines associated with suppression of pro-survival PDK1 signalling and engagement of apoptotic pathways. Our data support further investigation of this combination in RAS-mutant MM.

中文翻译：

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MEK与糖皮质激素受体联合靶向治疗RAS突变多发性骨髓瘤

尽管最近取得了治疗进展，但多发性骨髓瘤 (MM) 仍然无法治愈。RAS 突变通常与复发/难治性疾病相关。使用 MEK 抑制剂曲美替尼 (Tra) 靶向丝裂原活化蛋白激酶 (MAPK) 途径的努力受到毒性和耐药性发展的限制。地塞米松 (Dex) 是临床实践中常用的一种皮质类固醇，用于增强抗骨髓瘤治疗的疗效。因此，我们假设 Tra 和 Dex 的组合将在 RAS 突变 MM 中产生协同活性。通过流式细胞术和反相蛋白质阵列，使用细胞增殖测定、蛋白质印迹、膜联蛋白 V 和碘化丙啶染色分析人 MM 细胞系对药物治疗的反应。曲美替尼和地塞米松治疗 MM 的疗效。通过随时间测量肿瘤体积来评估 1S 异种移植模型。Tra/Dex 组合在 KRASG12A 突变系 MM.1S 和 RPMI-8226 中表现出协同细胞毒性。细胞凋亡的诱导与 MCL-1 表达降低和 BIM 表达增加有关。反相蛋白质组学阵列显示使用 Tra/Dex 组合抑制 FAK、PYK2、FLT3、NDRG1 和 4EBP1 磷酸化。值得注意的是，NDRG1 表达与对 Tra/Dex 的协同反应有关。MM 细胞对 PDK1 抑制和 IGF1 诱导的信号传导敏感，部分保护免受 Tra/Dex 处理，突出了该途径的重要性。在 MM.1S 肿瘤异种移植模型中，只有 Tra/Dex 的组合导致肿瘤生长的显着抑制。Tra/Dex 在 RAS 突变 MM 细胞系中的总体抗增殖活性与抑制促生存 PDK1 信号传导和参与凋亡途径相关。我们的数据支持在 RAS 突变 MM 中进一步研究这种组合。