Dual PAK4-NAMPT Inhibition Impacts Growth and Survival, and Increases Sensitivity to DNA-Damaging Agents in Waldenström Macroglobulinemia.
Dual PAK4-NAMPT Inhibition Impacts Growth and Survival, and Increases Sensitivity to DNA-Damaging Agents in Waldenström Macroglobulinemia.
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DOI：
10.1158/1078-0432.ccr-18-1776
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发表时间：
2019-01-01
期刊：
影响因子：
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通讯作者：
Fulciniti M
中科院分区：
文献类型：
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作者：
Li N;Lopez MA;Linares M;Kumar S;Oliva S;Martinez-Lopez J;Xu L;Xu Y;Perini T;Senapedis W;Baloglu E;Shammas MA;Hunter Z;Anderson KC;Treon SP;Munshi NC;Fulciniti M
p21活化激酶4（PAK 4）在包括多发性骨髓瘤（MM）在内的许多恶性肿瘤中发挥重要的生物学和功能作用。基于我们在MM中有希望的发现，我们在此表征了PAK 4在WM细胞中的表达和作用，以及PAK 4-NAMPT双重抑制剂（KPT-9274）对WM细胞生长和活力的影响。我们分析了WM细胞中PAK 4的mRNA和蛋白表达水平，并使用功能丧失方法研究其对WM细胞活力的贡献。我们进一步测试了KPT-9274对WM细胞生长和活力的体外和体内作用。我们在这里报告高水平的表达和功能作用的PAK 4在WM中，证明了shRNA介导的敲低;和显着的影响，KPT-9274 WM细胞的生长和活力。KPT-9274的生长抑制作用与PAK 4表达和NAMPT活性降低以及诱导细胞凋亡相关。有趣的是，在用KPT-9274处理的WM细胞系中，我们检测到对DNA损伤和修复基因的显著影响。此外，我们观察到，除了诱导DNA损伤，KPT-9274特异性地降低RAD 51和同源重组途径的双链断裂修复。结果，当与DNA烷基化剂苯达莫司汀和美法仑组合时，KPT-9274在体外和体内提供了WM细胞系和原代患者WM细胞中细胞活力的协同抑制。这些结果支持KPT-9274与DNA损伤剂联合治疗WM的临床研究。
p21-activated kinase 4 (PAK4) plays a significant biological and functional role in a number of malignancies, including multiple myeloma (MM). Based on our promising findings in MM, we here characterize PAK4 expression and role in WM cells, as well effect of dual PAK4-NAMPT inhibitor (KPT-9274) against WM cell growth and viability. We have analyzed mRNA and protein expression levels of PAK4 in WM cells, and used loss-of-function approach to investigate its contribution to WM cell viability. We have further tested the in vitro and in vivo effect of KPT-9274 against WM cell growth and viability. We report here high-level expression and functional role of PAK4 in WM, as demonstrated by shRNA-mediated knockdown; and significant impact of KPT-9274 on WM cell growth and viability. The growth inhibitory effect of KPT-9274 was associated with decreased PAK4 expression and NAMPT activity, as well as induction of apoptosis. Interestingly, in WM cell lines treated with KPT-9274, we detected a significant impact on DNA damage and repair genes. Moreover, we observed that apart from inducing DNA damage, KPT-9274 specifically decreased RAD51 and the double strand break repair by the homologous recombination pathway. As a result, when combined with a DNA alkylating agents bendamustine and melphalan, KPT-9274 provided a synergistic inhibition of cell viability in WM cell lines and primary patient WM cells in vitro and in vivo. These results support the clinical investigation of KPT-9274 in combination with DNA-damaging agent for treatment of WM.