Division of Cancer Therapeutics, The Institute of Cancer Research, London, SW7 3RP, UK.
The Royal Marsden NHS Foundation Trust, London, UK.
BMC Cancer. 2020 Mar 30;20(1):269. doi: 10.1186/s12885-020-06735-2.
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 KRAS 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.
尽管最近有了治疗上的进展，但多发性骨髓瘤（MM）仍然无法治愈。RAS 突变通常与复发/难治性疾病有关。用 MEK 抑制剂 trametinib（Tra）靶向丝裂原活化蛋白激酶（MAPK）通路的努力受到毒性和耐药性发展的限制。地塞米松（Dex）是一种临床上常用的皮质类固醇，用于增强抗骨髓瘤治疗的疗效。因此，我们假设 Tra 和 Dex 的联合应用将在 RAS 突变 MM 中产生协同活性。
用人 MM 细胞系进行药物治疗反应分析，采用细胞增殖测定、Western blot、流式细胞术 Annexin V 和碘化丙啶染色、反相蛋白阵列。通过测量随时间推移的肿瘤体积，评估 trametinib 和地塞米松治疗在 MM.1S 异种移植模型中的疗效。
Tra/Dex 联合用药在 KRAS 突变株 MM.1S 和 RPMI-8226 中表现出协同细胞毒性。凋亡的诱导与 MCL-1 表达降低和 BIM 表达增加有关。反相蛋白组学阵列显示，Tra/Dex 联合用药抑制了 FAK、PYK2、FLT3、NDRG1 和 4EBP1 的磷酸化。值得注意的是，NDRG1 表达与 Tra/Dex 的协同反应有关。MM 细胞对 PDK1 抑制和 IGF1 诱导的信号敏感，部分受到 Tra/Dex 治疗的保护，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 的联合应用才能显著抑制肿瘤生长。
Tra/Dex 总体上在 RAS 突变 MM 细胞系中表现出抗增殖活性，与抑制生存 PDK1 信号和激活凋亡途径有关。我们的数据支持进一步研究这种联合用药在 RAS 突变 MM 中的应用。
